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United States Patent 9,969,809
Kuo ,   et al. May 15, 2018

Therapeutic antibodies and their uses

Abstract

The present invention relates to antibodies, e.g., full length antibodies or antigen binding fragments thereof, that specifically bind to BCMA (B-Cell Maturation Antigen) and/or CD3 (Cluster of Differentiation 3). The invention also relates to antibody conjugates (e.g., antibody-drug-conjugates) comprising the BCMA antibodies, compositions comprising the BCMA antibodies, and methods of using the BCMA antibodies and their conjugates for treating conditions associated with cells expressing BCMA (e.g., cancer or autoimmune disease). The invention further relates to heteromultimeric antibodies that specifically bind to CD3 and a tumor cell antigen, (e.g., bispecific antibodies that specifically bind to CD3 and BCMA). Compositions comprising such heteromultimeric antibodies, methods for producing and purifying such heterodimeric antibodies, and their use in diagnostics and therapeutics are also provided.


Inventors: Kuo; Tracy Chia-Chien (San Mateo, CA), Chaparro Riggers; Javier Fernando (San Mateo, CA), Chen; Wei (Cupertino, CA), Chen; Amy Shaw-Ru (San Jose, CA), Pascua; Edward Derrick (Oakland, CA), Van Blarcom; Thomas John (Oakland, CA), Boustany; Leila Marie (Redwood City, CA), Ho; Weihsien (Belmont, CA), Yeung; Yik Andy (South San Francisco, CA), Strop; Pavel (San Mateo, CA), Rajpal; Arvind (San Francisco, CA)
Applicant:
Name City State Country Type

PFIZER INC.

New York

NY

US
Assignee: PFIZER INC. (New York, NY)
Family ID: 1000003295863
Appl. No.: 15/085,644
Filed: March 30, 2016


Prior Publication Data

Document IdentifierPublication Date
US 20160297885 A1Oct 13, 2016

Related U.S. Patent Documents

Application NumberFiling DatePatent NumberIssue Date
62146843Apr 13, 2015
62146504Apr 13, 2015
62301582Feb 29, 2016

Current U.S. Class: 1/1
Current CPC Class: A61K 47/6849 (20170801); A61K 47/6801 (20170801); C07K 16/2878 (20130101); A61K 31/454 (20130101); A61K 31/69 (20130101); A61K 31/704 (20130101); A61K 39/3955 (20130101); A61K 39/39558 (20130101); C07K 16/2803 (20130101); C07K 16/2809 (20130101); A61K 31/69 (20130101); A61K 31/704 (20130101); A61K 31/454 (20130101); C07K 2317/92 (20130101); C07K 2317/732 (20130101); C07K 2317/73 (20130101); C07K 2317/565 (20130101); C07K 2317/56 (20130101); A61K 2039/505 (20130101); C07K 2317/21 (20130101); C07K 2317/31 (20130101); A61K 2300/00 (20130101); A61K 2300/00 (20130101); A61K 2300/00 (20130101)
Current International Class: C07K 16/00 (20060101); C07K 16/28 (20060101); A61K 39/395 (20060101); A61K 31/454 (20060101); A61K 31/704 (20060101); A61K 31/69 (20060101); A61K 39/00 (20060101)

References Cited [Referenced By]

U.S. Patent Documents
7083785 August 2006 Browning et al.
9243058 January 2016 Armitage et al.
2008/0267965 October 2008 Kalled et al.
2015/0051266 February 2015 Kochenderfer
2015/0284467 October 2015 Lipp et al.
2015/0368351 December 2015 Vu et al.
2016/0297884 October 2016 Kuo et al.
Foreign Patent Documents
2762497 Aug 2014 EP
3023437 May 2016 EP
3029068 Jun 2016 EP
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Other References

Ramadoss et al. (J. Am. Chem. Soc. 2015, 137, 5288-5291; cited on IDS filed Apr. 4, 2017) (Year: 2015). cited by examiner .
International Search Report for International Application No. PCT/IB2016/051801 dated Jun. 6, 2016. cited by applicant .
Ramadoss, N., et al., "An Anti-B Cell Maturation Antigen Bispecific Antibody for Multiple Myeloma," Journal of the American Chemical Society, 2015, 5288-5291, vol. 137, No. 16. cited by applicant .
Written Opinion for International Application No. PCT/IB2016/051801 dated Jun. 6, 2016. cited by applicant.

Primary Examiner: Goddard; Laura B
Assistant Examiner: Natarajan; Meera
Attorney, Agent or Firm: Yeh; Jenny J.

Parent Case Text



RELATED APPLICATIONS

This application claims the benefits of U.S. Provisional Application No. 62/146,843 filed Apr. 13, 2015, U.S. Provisional Application No. 62/146,504 filed Apr. 13, 2015, and U.S. Provisional Application No. 62/301,582 filed Feb. 29, 2016, all of which are hereby incorporated by reference in their entireties.
Claims



The invention claimed is:

1. A bispecific antibody wherein the bispecific antibody is a full-length antibody, comprising a first antibody variable domain of the bispecific antibody capable of recruiting the activity of a human immune effector cell by specifically binding to an effector antigen located on the human immune effector cell, and comprising a second antibody variable domain of the bispecific antibody capable of specifically binding to a target antigen, wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398, or 400; and e a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399.

2. The bispecific antibody of claim 1, wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449, or 450; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, 440, or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453.

3. The bispecific antibody of claim 2, wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 112; and a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 38.

4. The bispecific antibody of claim 1, wherein the second antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO:150, 151, 152, 156, or 157; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 169, 154, 194, 159, 195, 196, 162, 158, 198, 177, 178, 199, 200, 201, 202, 203, 204, 206, 207, 208, 172, 359, or 360; and (iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 155, 161, 197, 205, 164, or 361; and wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297, or 299; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221 or 362; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 211, 225, 272, 274, 276, 278, 280, 281, 282, 284, 286, 288, 289, 291, 293, 294, 229, 296, 298, or 300.

5. The bispecific antibody of claim 4, wherein the a. first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 407, or 4081 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336, 417, 404, or 405; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335 or 406; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439; and the b. the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 151, 156, or 157; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 158 or 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and/e wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225.

6. The bispecific antibody of claim 1, wherein both the first and the second antibody variable domains of the antibody comprise amino acid modifications at positions 223, 225, and 228 in the hinge region and at position 409 or 368 (EU numbering scheme) in the CH3 region of a human IgG2 (SEQ ID NO: 493).

7. The bispecific antibody of claim 6, further comprising an amino acid modification at position 265 of the human IgG2.

8. A pharmaceutical composition comprising the bispecific antibody of claim 1.
Description



REFERENCE TO SEQUENCE LISTING

This application is being filed electronically via EFS-Web and includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled "PC72209A_Updated_SEQListing_ST25.txt" created on Dec. 21, 2017 and having a size of 294 KB. The sequence listing contained in this .txt file is part of the specification and is incorporated herein by reference in its entirety.

FIELD

The present invention relates to antibodies, e.g., full length antibodies or antigen binding fragments thereof, that specifically bind to BCMA (B-Cell Maturation Antigen) and/or CD3 (Cluster of Differentiation 3). The invention also relates to antibody conjugates (e.g., antibody-drug-conjugates) comprising the BCMA antibodies, compositions comprising the BCMA antibodies, and methods of using the BCMA antibodies and their conjugates for treating conditions associated with cells expressing BCMA (e.g., cancer or autoimmune disease). The invention further relates to heteromultimeric antibodies that specifically bind to CD3 and a tumor cell antigen, (e.g., bispecific antibodies that specifically bind to CD3 and BCMA). Compositions comprising such heteromultimeric antibodies, methods for producing and purifying such heterodimeric antibodies, and their use in diagnostics and therapeutics are also provided.

BACKGROUND

B-cell maturation antigen (BCMA, CD269, or TNFRSF17) is a member of the tumor necrosis factor receptor (TNFR) superfamily. BCMA was identified in a malignant human T cell lymphoma containing a t(4;16) translocation. The gene is selectively expressed in the B-cell lineage with the highest expression in plasma blasts and plasma cells, antibody secreting cells. BCMA binds two ligands, B-cell activation factor (BAFF) (also called B-lymphocyte stimulator (BLyS) and APOL-related leukocyte expressed ligand (TALL-1)) and a proliferation-inducing ligand (APRIL) with affinity of 1 uM and 16 nM, respectively. Binding of APRIL or BAFF to BCMA promotes a signaling cascade involving NF-kappa B, Elk-1, c-Jun N-terminal kinase and the p38 mitogen-activated protein kinase, which produce signals for cell survival and proliferation.

BCMA is also expressed on malignant B cells and several cancers that involve B lymphocytes including multiple myeloma, plasmacytoma, Hodgkin's Lymphoma, and chronic lymphocytic leukemia. In autoimmune diseases where plasmablasts are involved such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, BCMA expressing antibody-producing cells secrete autoantibodies that attack self.

In the case of multiple myeloma, about 24,000 new cases are newly diagnosed in the United States each year, and this number represents about 15% of the newly diagnosed hematological cancers in the United States. An average of 11,000 deaths result from multiple myeloma each year, and the average 5-year survival rate is about 44%, with median survival of 50-55 months. Current treatment for multiple myeloma is focused on plasma cells apoptosis and/or decreasing osteoclast activity (e.g., chemotherapy, thalidomide, lenalidomide, bisphosphonates, and/or proteasome inhibitors such as bortezomib (VELCADE.RTM.) or carfilzomib). However, multiple myeloma remains an incurable disease, and almost all patients have developed resistance to these agents and eventually relapse. Accordingly, an alternative treatment to multiple myeloma, such as using an anti-BCMA antagonist including antibodies and other immunotherapeutic agents (e.g. bispecific antibodies or antibody-drug conjugates), would make a superior therapeutic agent.

SUMMARY

The invention disclosed herein is directed to therapeutic antibodies that bind to BCMA and/or CD3. Antibody conjugates (e.g., antibody-drug conjugates) comprising BCMA are also provided. Further, the heteromultimeric antibodies (e.g., bispecific antibodies) that specifically bind to CD3 and a tumor cell antigen (e.g., bispecific antibodies that specifically bind to CD3 and BCMA) are also provided.

In one aspect, the invention provides an isolated antibody, or an antigen binding fragment thereof, which specifically binds to B-Cell Maturation Antigen (BCMA), wherein the antibody comprises (a) a heavy chain variable (VH) region comprising (i) a VH complementary determining region one (CDR1) comprising the sequence SYX.sub.1MX.sub.2, wherein X.sub.1 is A or P; and X.sub.2 is T, N, or S (SEQ ID NO: 301), GFTFX.sub.1SY, wherein X.sub.1 is G or S (SEQ ID NO: 302), or GFTFX.sub.1SYX.sub.2MX.sub.3, wherein X.sub.1 is G or S, X.sub.2 is A or P; and X.sub.3 is T, N, or S (SEQ ID NO: 303); (ii) a VH CDR2 comprising the sequence AX.sub.1X.sub.2X.sub.3X.sub.4GX.sub.5X.sub.6X.sub.7X.sub.8YADX.sub.9X.sub- .10KG, wherein X.sub.1 is I, V, T, H, L, A, or C; X.sub.2 is S, D, G, T, I, L, F, M, or V; X.sub.3 is G, Y, L, H, D, A, S, or M; X.sub.4 is S, Q, T, A, F, or W; X.sub.5 is G or T; X.sub.6 is N, S, P, Y, W, or F; X.sub.7 is S, T, I, L, T, A, R, V, K, G, or C; X.sub.8 is F, Y, P, W, H, or G; X.sub.9 is V, R, or L; and X.sub.10 is G or T (SEQ ID NO: 305), or X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6, wherein X.sub.1 is S, V, I, D, G, T, L, F, or M; X.sub.2 is G, Y, L, H, D, A, S, or M; X.sub.3 is S, G, F, or W; X.sub.4 is G or S; X.sub.5 is G or T; and X.sub.6 is N, S, P, Y, or W (SEQ ID NO: 306); and iii) a VH CDR3 comprising the sequence VSPIX.sub.1X.sub.2X.sub.3X.sub.4, wherein X.sub.1 is A or Y; X.sub.2 is A or S; and X.sub.3 is G, Q, L, P, or E (SEQ ID NO: 307), or YWPMX.sub.1X.sub.2, wherein X.sub.1 is D, S, T, or A; and X.sub.2 is I, S, L, P, or D (SEQ ID NO: 308); and/or (b) a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9X.sub.10X.- sub.11X.sub.12, wherein X.sub.1 is R, G, W, A, or C; X.sub.2 is A, P, G, L, C, or S; X.sub.3 is S, G, or R; X.sub.4 is Q, C, E, V, or I; X.sub.5 is S, P, G, A, R, or D; X.sub.6 is V, G, I, or L; X.sub.7 is S, E, D, P, or G; X.sub.8 is S, P, F, A, M, E, V, N, D, or Y; X.sub.9 is I, T, V, E, S, A, M, Q, Y, H, R, or F; X.sub.10 is Y or F; X.sub.11 is L, W, or P; and X.sub.12 is A, S, or G (SEQ ID NO: 309); (ii) a VL CDR2 comprising the sequence X.sub.1ASX.sub.2RAX.sub.3, wherein X.sub.1 is G or D; X.sub.2 is S or I; and X.sub.3 is T or P (SEQ ID NO: 310); and (iii) a VL CDR3 comprising the sequence QQYX.sub.1X.sub.2X.sub.3PX.sub.4T, wherein X.sub.1 is G, Q, E, L, F, A, S, M, K, R, or Y; X.sub.2 is S, R, T, G, V, F, Y, D, A, H, V, E, K, or C; X.sub.3 is W, F, or S; and X.sub.4 is L or I (SEQ ID NO: 311), or QQYX.sub.1X.sub.2X.sub.3PX.sub.4, wherein X.sub.1 is G, Q, E, L, F, A, S, M, R, K, or Y; X.sub.2 is S, R, T, G, R, V, D, A, H, E, K, C, F, or Y; X.sub.3 is W, S, or F; and X.sub.4 is L or I (SEQ ID NO: 312).

In another aspect, the invention provides an isolated antibody, or an antigen binding fragment thereof, which specifically binds to BCMA, wherein the antibody comprises: a VH region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 125, 127, 313, 314, 363, or 365; and/or a VL region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315, 316, or 364. In some embodiments, the VH region comprises (i) a VH CDR1 comprising SEQ ID NO:150, 151, 152, 156, or 157; (ii) a VH CDR2 comprising SEQ ID NO: 169, 154, 194, 159, 195, 196, 162, 158, 198, 177, 178, 199, 200, 201, 202, 203, 204, 206, 207, 208, 172, 203, or 204; and (iii) a VH CDR3 comprising SEQ ID NO: 155, 161, 197, 205, or 164; and/or wherein the VL region comprises (i) a VL CDR1 comprising SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297, or 299; (ii) a VL CDR2 comprising SEQ ID NO: 221; and (iii) a VL CDR3 comprising SEQ ID NO: 225, 272, 274, 276, 278, 280, 281, 282, 284, 286, 288, 289, 291, 293, 294, 229, 296, 298, or 300. In some embodiments, the VH region comprises the sequence shown in SEQ ID NO: 112 or a variant with one or several conservative amino acid substitutions in residues that are not within a CDR and/or the VL region comprises the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof with one or several amino acid substitutions in amino acids that are not within a CDR. In some embodiments, the antibody comprises a light chain comprising the sequence shown in SEQ ID NO: 357 and a heavy chain comprising the sequence shown in SEQ ID NO: 358. In some embodiments, the antibody comprises a VH region produced by the expression vector with ATCC Accession No. PTA-122094. In some embodiments, the antibody comprises a VL region produced by the expression vector with ATCC Accession No. PTA-122093.

In another aspect, the invention provides an isolated antibody comprising an acyl donor glutamine-containing tag engineered at a specific site of the BCMA antibody of the present invention. In some embodiments, the tag comprises an amino acid sequence selected from the group consisting of Q, LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO: 455), GGGLLQGG (SEQ ID NO: 456), GLLQG (SEQ ID NO: 457), LLQ, GSPLAQSHGG (SEQ ID NO: 458), GLLQGGG (SEQ ID NO: 459), GLLQGG (SEQ ID NO: 460), GLLQ (SEQ ID NO: 461), LLQLLQGA (SEQ ID NO: 462), LLQGA (SEQ ID NO: 463), LLQYQGA (SEQ ID NO: 464), LLQGSG (SEQ ID NO: 465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479), LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483), and LLQLQG (SEQ ID NO: 484).

In one variation, the invention provides an isolated antibody comprising an acyl donor glutamine-containing tag and an amino acid modification at position 222, 340, or 370 of the BCMA antibody of the present invention. In some embodiments, the amino acid modification is a substitution from lysine to arginine.

In some embodiments, the BCMA antibody of the present invention further comprises a linker. In some embodiments, the linker is selected from the group consisting of Ac-Lys-Gly (acetyl-lysine-glycine), aminocaproic acid, Ac-Lys-.beta.-Ala (acetyl-lysine-.beta.-alanine), amino-PEG2 (polyethylene glycol)-C2, amino-PEG3-C2, amino-PEG6-C2, Ac-Lys-Val-Cit-PABC (acetyl-lysine-valine-citrulline-p-aminobenzyloxycarbonyl), amino-PEG6-C2-Val-Cit-PABC, am inocaproyl-Val-Cit-PABC, [(3R,5R)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-- Val-Cit-PABC, [(3S,5S)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-- Val-Cit-PABC, putrescine, and Ac-Lys-putrescine.

In another aspect, the invention provides a conjugate of the BCMA antibody or the antigen binding fragment as described herein, wherein the antibody or the antigen binding fragment is conjugated to an agent, wherein the agent is selected from the group consisting of a cytotoxic agent, an immunomodulating agent, an imaging agent, a therapeutic protein, a biopolymer, and an oligonucleotide. In some embodiments, the agent is a cytotoxic agent including, but not limited to, an anthracycline, an auristatin, a camptothecin, a combretastatin, a dolastatin, a duocarmycin, an enediyne, a geldanamycin, an indolino-benzodiazepine dimer, a maytansine, a puromycin, a pyrrolobenzodiazepine dimer, a taxane, a vinca alkaloid, a tubulysin, a hemiasterlin, a spliceostatin, a pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof. For example, the cytotoxic agent is MMAD (Monomethyl Auristatin D), 0101 (2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-me- thyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrol- idin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide), 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methox- y-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinamide), 0131 (2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methox- y-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide), or 0121 (2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy-1-o- xo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-- yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide).

In some embodiments, the present invention provides a conjugate comprising the formula: antibody-(acyl donor glutamine-containing tag)-(linker)-(cytotoxic agent). In some embodiments, the acyl donor glutamine-containing tag comprises an amino acid sequence LLQG (SEQ ID NO: 319) and/or GGLLQGPP (SEQ ID NO: 339) and wherein the linker comprises acetyl-lysine-valine-citrulline-p-aminobenzyloxycarbonyl or amino-PEG6-C2. In some embodiments, the conjugate is selected from the group consisting of 1) antibody-GGLLQGPP (SEQ ID NO: 339)-(acetyl-lysine-valine-citrulline-p-aminobenzyloxycarbonyl (AcLys-VC-PABC))-0101; 2) antibody-LLQG (SEQ ID NO: 319)-amino-PEG6-C2-0131; and 3) antibody-LLQG (SEQ ID NO: 319)-amino-PEG6-C2-3377. In some embodiments, the conjugate further comprises an amino acid substitution from lysine to arginine at antibody position 222. In some embodiments, the conjugate further comprises amino acid substitutions at antibody position N297Q or N297A.

In another aspect, provided is a method of producing the BCMA antibody as described herein, comprising culturing the host cell under conditions that result in production of the BCMA antibody, and isolating the BCMA antibody from the host cell or culture.

In another aspect, the invention provides a use of the BCMA antibodies or the BCMA antibody conjugates as described herein in the manufacture of a medicament for treating a condition (e.g., cancer or autoimmune disorder) associated with BCMA expression. In some embodiments, provided is a use of the BCMA antibodies or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting tumor growth or progression. In some embodiments, provided is a use of the BCMA antibodies or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting metastasis of malignant cells expressing BCMA. In some embodiments, provided is a use of the BCMA antibodies or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inducing tumor regression.

In another aspect, the invention provides an isolated antibody, or an antigen binding fragment thereof, which specifically binds to CD3, wherein the antibody comprises a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398, or 400; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399. In some embodiments, the antibody comprises a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387. In some embodiments, the VH region comprises (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449, or 450; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, or 440, 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. In some embodiments, the VH region comprises (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 407, or 408 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336, 404, 405, or 417; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335 or 406; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439. In some embodiments, the antibody comprises a VH region produced by the expression vector with ATCC Accession No. PTA-122513. In some embodiments, the antibody comprises a VL region produced by the expression vector with ATCC Accession No. PTA-122512.

In another aspect, provided is an isolated antibody which specifically binds to CD3 and competes with the anti-CD3 antibody of the present invention as described herein.

In another aspect, the invention provides a bispecific antibody wherein the bispecific antibody is a full-length human antibody, comprising a first antibody variable domain of the bispecific antibody capable of recruiting the activity of a human immune effector cell by specifically binding to an effector antigen located on the human immune effector cell, and comprising a second antibody variable domain of the bispecific antibody capable of specifically binding to a target antigen, wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398, or 400; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399. In some embodiments, the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449, or 450; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, or 440, 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. In some embodiments, the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 112; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 38.

In some embodiments, the second antibody variable domain comprises (a) a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence SYX.sub.1MX.sub.2, wherein X.sub.1 is A or P; and X.sub.2 is T, N, or S (SEQ ID NO: 301), GFTFX.sub.1SY, wherein X.sub.1 is G or S (SEQ ID NO: 302), or GFTFX.sub.1SYX.sub.2MX.sub.3, wherein X.sub.1 is G or S, X.sub.2 is A or P; and X.sub.3 is T, N, or S (SEQ ID NO: 303); (ii) a VH CDR2 comprising the sequence AX.sub.1X.sub.2X.sub.3X.sub.4GX.sub.5X.sub.6X.sub.7X.sub.8YADX.sub.9X.sub- .10KG, wherein X.sub.1 is I, V, T, H, L, A, or C; X.sub.2 is S, D, G, T, I, L, F, M, or V; X.sub.3 is G, Y, L, H, D, A, S, or M; X.sub.4 is S, Q, T, A, F, or W; X.sub.5 is G or T; X.sub.6 is N, S, P, Y, W, or F; X.sub.7 is S, T, I, L, T, A, R, V, K, G, or C; X.sub.8 is F, Y, P, W, H, or G; X.sub.9 is V, R, or L; and X.sub.10 is G or T (SEQ ID NO: 305), or X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6, wherein X.sub.1 is S, V, I, D, G, T, L, F, or M; X.sub.2 is G, Y, L, H, D, A, S, or M; X.sub.3 is S, G, F, or W; X.sub.4 is G or S; X.sub.5 is G or T; and X.sub.6 is N, S, P, Y, or W (SEQ ID NO: 306); and iii) a VH CDR3 comprising the sequence VSPIX.sub.1X.sub.2X.sub.3X.sub.4 wherein X.sub.1 is A or Y; X.sub.2 is A or S; and X.sub.3 is G, Q, L, P, or E (SEQ ID NO: 307), or YWPMX.sub.1X.sub.2, wherein X.sub.1 is D, S, T, or A; and X.sub.2 is I, S, L, P, or D (SEQ ID NO: 308); and/or (b) a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9X.sub.10X.- sub.11X.sub.12, wherein X.sub.1 is R, G, W, A, or C; X.sub.2 is A, P, G, L, C, or S; X.sub.3 is S, G, or R; X.sub.4 is Q, C, E, V, or I; X.sub.5 is S, L, P, G, A, R, or D; X.sub.6 is V, G, or I; X.sub.7 is S, E, D, or P; X.sub.8 is S, P, F, A, M, E, V, N, D, or Y; X.sub.9 is I, T, V, E, S, A, M, Q, Y, H, or R; X.sub.10 is Y or F; X.sub.11 is L, W, or P; and X.sub.12 is A, S, or G (SEQ ID NO: 309); (ii) a VL CDR2 comprising the sequence X.sub.1ASX.sub.2RAX.sub.3, wherein X.sub.1 is G or D; X.sub.2 is S or I; and X.sub.3 is T or P (SEQ ID NO: 310); and (iii) a VL CDR3 comprising the sequence QQYX.sub.1X.sub.2X.sub.3PX.sub.4T, wherein X.sub.1 is G, Q, E, L, F, A, S, M, K, R, or Y; X.sub.2 is S, R, T, G, V, F, Y, D, A, H, V, E, K, or C; X.sub.3 is W, F, or S; and X.sub.4 is L or I (SEQ ID NO: 311), or QQYX.sub.1X.sub.2X.sub.3PX.sub.4, wherein X.sub.1 is G, Q, E, L, F, A, S, M, R, K, or Y; X.sub.2 is S, R, T, G, R, V, D, A, H, E, K, C, F, or Y; X.sub.3 is W, S, or F; and X.sub.4 is L or I (SEQ ID NO: 312). In some embodiments, the second antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 150, 151, 152, 156, 157, 348, 349, 353, 354, or 355; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 169, 154, 194, 159, 195, 196, 162, 158, 198, 177, 178, 199, 200, 201, 202, 203, 204, 206, 207, 208, 172, 203, 204, 350, 351, 356 or 357; and (iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 155, 161, 197, 205,164, or 352, or 358; and/or wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297, 299, or 361; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221, 359 or 362; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 211, 225, 272, 274, 276, 278, 280, 281, 282, 284, 286, 288, 289, 291, 293, 294, 229, 296, 298, 300 or 360.

In some embodiments, (a) the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 407, or 408(ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336, 417, 404, or 405; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335 or 406; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439; and (b) the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 151, 156, or 157; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 158 or 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and/or wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225.

In some embodiments, both the first and the second antibody variable domains of the bispecific antibody comprise amino acid modifications at positions 223, 225, and 228 in the hinge region and at position 409 or 368 (EU numbering scheme) in the CH3 region of a human IgG2 (SEQ ID NO: 493). In some embodiments, the bispecific antibody as described herein further comprises an amino acid modification at position 265 of the human IgG2.

In another aspect, the invention provides pharmaceutical compositions comprising any of the antibodies (e.g., BCMA, CD3, or bispecific) or the conjugates thereof (e.g., BCMA antibody-drug conjugate) described herein.

In another aspect, the invention also provides cell lines that recombinantly produce any of the antibodies (e.g., BCMA, CD3, or bispecific) or the conjugates thereof (e.g., BCMA antibody-drug conjugate) described herein.

In another aspect, the invention also provides nucleic acids encoding any of the antibodies (e.g., BCMA, CD3, or bispecific) or the conjugates thereof (e.g., BCMA antibody-drug conjugate) described herein. The invention also provides nucleic acids encoding a heavy chain variable region and/or a light chain variable region of any of these antibodies described herein.

The invention also provides kits comprising an effective amount of any of the antibodies (e.g., BCMA, CD3, or bispecific) or the conjugates thereof (e.g., BCMA antibody-drug conjugate) described herein.

The invention also provides methods of treating a condition (e.g., tumor growth/progression inhibition; metastasis of malignant cells expressing BCMA inhibition; tumor regression induction in subjects with malignant cells expressing BCMA) in subjects in need thereof comprising providing the isolated antibodies (e.g., BCMA) or binding fragments, bispecific antibodies (BCMA-CD3 bispecifics), or the conjugates thereof (e.g., BCMA antibody-drug conjugates) thereof described herein and administering said antibodies or conjugates to said subject.

Also provided are methods of treating a condition associated with malignant cells expressing a tumor antigen in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical compositions of the invention. In some embodiments, the condition is cancer. In some embodiments, the cancer is a B-cell related cancer selecting from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte predominant Hodgkin's lymphoma, Kahler's disease and Myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulienemia, diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmactyic lymphoma, Waldenstrom macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell/histiocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell related lymphoma. In some embodiments, the condition is an autoimmune disorder, such as systemic lupus erythematosus or rheumatoid arthritis.

In some embodiments, the antibodies described herein comprise a constant region. In some embodiments, the antibodies described herein are of the human IgG1, IgG2 or IgG2.DELTA.a, IgG3, or IgG4 subclass. In some embodiments, the antibodies described herein comprise a glycosylated constant region. In some embodiments, the antibodies described herein comprise a constant region having increased binding affinity to one or more human Fc gamma receptor(s).

BRIEF DESCRIPTION OF THE FIGURES/DRAWINGS

FIG. 1A-FIG. 1D depict the double-referenced sensorgrams with fit curves for interactions between selected anti-BCMA antibodies of the present invention and human BCMA.

FIG. 2 depicts in vivo efficacy studies of various anti-BCMA ADCs in the MM1S orthotopic multiple myeloma model, including P6E01_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5A2_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5C1_VHVL-AcLys-Val-Cit-PABC-Aur0101; P4G4-AcLys-Val-Cit-PABC-Aur0101; and P1A11-AcLys-Val-Cit-PABC-Aur0101. NNC is a negative control non-BCMA antibody. "LCQ05" and "LCQ04" correspond to glutamine-containing transglutaminase tag SEQ ID NOs: 474 and 475, respectively.

FIG. 3 depicts in vivo efficacy of the anti-BCMA ADCs in the MM1S orthotopic multiple myeloma model, including L3.PY/P6E01 antibody conjugated with 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-1101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101. NNC is a control non-BCMA antibody. "LCQ05" and H7c correspond to glutamine-containing transglutaminase tag SEQ ID NO: 474 and SEQ ID NO: 454, respectively

FIG. 4 also depicts in vivo efficacy of the anti-BCMA ADCs in the MM1S orthotopic multiple myeloma model, including L3.PY/P6E01 antibody conjugated with 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101. NNC is a control non-BCMA antibody (antibody-N297Q/K222R-AcLys-VC-PABC-0101). "LCQ05" and H7c correspond to glutamine-containing transglutaminase tag SEQ ID NO: 474 and SEQ ID NO: 454, respectively.

FIG. 5 also depicts in vivo efficacy of an anti-BCMA ADC in the MM1S orthotopic multiple myeloma model. Anti-BCMA antibody COMBO_Rd4_0.6 nM-C29 ("Combo C29 DI) is conjugated to H7c/N297A/K222R-amino-PEG6-C2-131 at doses ranging from 0.1 mg/kg, 0.38 mg/kg, 0.75 mg/kg, 1.5 mg/kg in comparison to NNC, a control non-BCMA antibody (antibody-N297Q/K222R-AcLys-VC-PABC-0101) at 3 mg/kg. H7c correspond to glutamine-containing transglutaminase tag SEQ ID NO: 454.

FIG. 6A-FIG. 6F depict the in vivo efficacy of an anti-CD3/anti-CD20 bispecific antibody in cynomolgus monkeys. B cell depletion following a single dose of bispecific antibody is shown as a percentage of prestudy counts.

FIG. 7A-FIG. 7F depict the in vivo efficacy of an anti-CD3/anti-CD20 bispecific antibody in cynomolgus monkeys. CD8+ T cell kinetics were tracked following a single dose of bispecific antibody.

FIG. 8A and FIG. 8B depict the in vivo efficacy of an anti-CD3/anti-CD20 bispecific antibody in cynomolgus monkeys. The effect of the monovalent CD3 antibody on T cell kinetics and proliferation was analyzed.

FIG. 9A-FIG. 9D depict the in vivo efficacy of an anti-CD3/anti-CD20 bispecific antibody in cynomolgus monkeys. The effect of anti-CD3 arm affinity on B cell depletion was analyzed.

FIGS. 10A and 10B show that the selected anti-CD3 antibodies had Thymidine incorporation reading on human and cynomolgus PBMC.

FIG. 11A-FIG. 11D show that all human anti-EpCam_h2B4 bispecific antibodies have cell killing activity on in vitro setting.

FIG. 12 shows that a single dose of human anti-BCMA/CD3 bispecific antibody resulted in tumor regression in a dose-dependent manner in an orthotopic MM1.S myeloma model.

FIG. 13 shows that two doses of human anti-BCMA/CD3 bispecific antibody resulted in increased tumor regression in an orthotopic Molp8 myeloma model.

FIG. 14 shows that anti-BCMA/CD3 bispecific antibody alone or in combination with standard of care for multiple myeloma (lenalidomide or bortezomib) is more efficacious than lenalidomide and bortezomib combined in orthotopic Molp8 tumor model.

FIG. 15A-FIG. 15C, respectively, show that carfilzomib, lenalidomide, and doxorubicin do not have a negative effect on the function of the anti-BCMA/CD3 bispecific antibody on OPM2 cells as compared to the anti-BCMA/CD3 bispecific antibody alone.

FIG. 16 shows synergistic effects on the function of anti-BCMA/CD3 bispecific antibody when combined with carfilzomib and lenalidomide in comparison to each molecule alone.

DETAILED DESCRIPTION

The invention disclosed herein provides antibodies and antibody conjugates (e.g., antibody-drug conjugates) that specifically bind to BCMA (e.g., human BCMA). The invention also provides polynucleotides encoding these antibodies and conjugates, compositions comprising these antibodies and conjugates, and methods of making these antibodies and conjugates. Further, the invention disclosed herein provides antibodies that specifically bind to CD3 (e.g., human CD3) as well as heterodimeric antibodies (e.g., bispecific antibodies) that specifically bind to CD3 and a tumor antigen (e.g., BCMA). The invention also provides polynucleotides encoding these antibodies, compositions comprising these antibodies, and methods of making and using these antibodies. The invention further provides methods for treating a condition associated with malignant BCMA expression in a subject, such as cancer or autoimmune disease, using the antibodies (e.g., BCMA, CD3, or bispecific antibody) or conjugates thereof (BCMA antibody-drug conjugates) as described herein.

General Techniques

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995).

Definitions

An "antibody" is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab').sub.2, Fv), single chain (ScFv) and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or subclass thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

The term "antigen binding fragment" or "antigen binding portion" of an antibody, as used herein, refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen (e.g., BCMA or CD3). Antigen binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term "antigen binding fragment" of an antibody include Fab; Fab'; F(ab').sub.2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single domain antibody (dAb) fragment (Ward et al., Nature 341:544-546, 1989), and an isolated complementarity determining region (CDR).

An antibody, an antibody conjugate, or a polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to a target (e.g., BCMA protein or CD3 protein) is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a BCMA epitope or CD3 epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other BCMA epitopes, non-BCMA epitopes, CD3 epitopes, or non-CD3 epitopes. It is also understood that by reading this definition, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md.)); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948). As used herein, a CDR may refer to CDRs defined by either approach or by a combination of both approaches.

A "CDR" of a variable domain are amino acid residues within the variable region that are identified in accordance with the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, and/or conformational definitions or any method of CDR determination well known in the art. Antibody CDRs may be identified as the hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. The positions of the CDRs may also be identified as the structural loop structures originally described by Chothia and others. See, e.g., Chothia et al., Nature 342:877-883, 1989. Other approaches to CDR identification include the "AbM definition," which is a compromise between Kabat and Chothia and is derived using Oxford Molecular's AbM antibody modeling software (now Accelrys.RTM.), or the "contact definition" of CDRs based on observed antigen contacts, set forth in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to herein as the "conformational definition" of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.

As used herein, "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, Nature 256:495, 1975, or may be made by recombinant DNA methods such as described in U.S. Pat. No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., Nature 348:552-554, 1990, for example.

As used herein, "humanized" antibody refers to forms of non-human (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab').sub.2 or other antigen binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. Preferably, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Preferred are antibodies having Fc regions modified as described in WO 99/58572. Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, or CDR H3) which are altered with respect to the original antibody, which are also termed one or more CDRs "derived from" one or more CDRs from the original antibody.

As used herein, "human antibody" means an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and/or which has been made using any of the techniques for making human antibodies known to those skilled in the art or disclosed herein. This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody comprising murine light chain and human heavy chain polypeptides. Human antibodies can be produced using various techniques known in the art. In one embodiment, the human antibody is selected from a phage library, where that phage library expresses human antibodies (Vaughan et al., Nature Biotechnology, 14:309-314, 1996; Sheets et al., Proc. Natl. Acad. Sci. (USA) 95:6157-6162, 1998; Hoogenboom and Winter, J. Mol. Biol., 227:381, 1991; Marks et al., J. Mol. Biol., 222:581, 1991). Human antibodies can also be made by immunization of animals into which human immunoglobulin loci have been transgenically introduced in place of the endogenous loci, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. This approach is described in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, the human antibody may be prepared by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes may be recovered from an individual or from single cell cloning of the cDNA, or may have been immunized in vitro). See, e.g., Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J. Immunol., 147 (1):86-95, 1991; and U.S. Pat. No. 5,750,373.

The term "chimeric antibody" is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

The terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably herein to refer to chains of amino acids of any length, preferably, relatively short (e.g., 10-100 amino acids). The chain may be linear or branched, it may comprise modified amino acids, and/or may be interrupted by non-amino acids. The terms also encompass an amino acid chain that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood that the polypeptides can occur as single chains or associated chains.

A "monovalent antibody" comprises one antigen binding site per molecule (e.g., IgG or Fab). In some instances, a monovalent antibody can have more than one antigen binding sites, but the binding sites are from different antigens.

A "monospecific antibody" comprises two identical antigen binding sites per molecule (e.g. IgG) such that the two binding sites bind identical epitope on the antigen. Thus, they compete with each other on binding to one antigen molecule. Most antibodies found in nature are monospecific. In some instances, a monospecific antibody can also be a monovalent antibody (e.g. Fab)

A "bivalent antibody" comprises two antigen binding sites per molecule (e.g., IgG). In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific.

A "bispecific" or "dual-specific" is a hybrid antibody having two different antigen binding sites. The two antigen binding sites of a bispecific antibody bind to two different epitopes, which may reside on the same or different protein targets.

A "bifunctional" is antibody is an antibody having identical antigen binding sites (i.e., identical amino acid sequences) in the two arms but each binding site can recognize two different antigens.

A "heteromultimer", "heteromultimeric complex", or "heteromultimeric polypeptide" is a molecule comprising at least a first polypeptide and a second polypeptide, wherein the second polypeptide differs in amino acid sequence from the first polypeptide by at least one amino acid residue. The heteromultimer can comprise a "heterodimer" formed by the first and second polypeptide or can form higher order tertiary structures where polypeptides in addition to the first and second polypeptide are present.

A "heterodimer," "heterodimeric protein," "heterodimeric complex," or "heteromultimeric polypeptide" is a molecule comprising a first polypeptide and a second polypeptide, wherein the second polypeptide differs in amino acid sequence from the first polypeptide by at least one amino acid residue.

The "hinge region," "hinge sequence", and variations thereof, as used herein, includes the meaning known in the art, which is illustrated in, for example, Janeway et al., ImmunoBiology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999); Bloom et al., Protein Science (1997), 6:407-415; Humphreys et al., J. Immunol. Methods (1997), 209:193-202.

The "immunoglobulin-like hinge region," "immunoglobulin-like hinge sequence," and variations thereof, as used herein, refer to the hinge region and hinge sequence of an immunoglobulin-like or an antibody-like molecule (e.g., immunoadhesins). In some embodiments, the immunoglobulin-like hinge region can be from or derived from any IgG1, IgG2, IgG3, or IgG4 subtype, or from IgA, IgE, IgD or IgM, including chimeric forms thereof, e.g., a chimeric IgG1/2 hinge region.

The term "immune effector cell" or "effector cell as used herein refers to a cell within the natural repertoire of cells in the human immune system which can be activated to affect the viability of a target cell. The viability of a target cell can include cell survival, proliferation, and/or ability to interact with other cells.

Antibodies of the invention can be produced using techniques well known in the art, e.g., recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies or other technologies readily known in the art (see, for example, Jayasena, S. D., Clin. Chem., 45: 1628-50, 1999 and Fellouse, F. A., et al, J. Mol. Biol., 373(4):924-40, 2007).

As known in the art, "polynucleotide," or "nucleic acid," as used interchangeably herein, refer to chains of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the chain. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, alpha- or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S("thioate"), P(S)S ("dithioate"), (O)NR.sub.2 ("amidate"), P(O)R, P(O)OR', CO or CH.sub.2 ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (--O--) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

As known in the art a "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

As used herein, "substantially pure" refers to material which is at least 50% pure (i.e., free from contaminants), more preferably, at least 90% pure, more preferably, at least 95% pure, yet more preferably, at least 98% pure, and most preferably, at least 99% pure.

A "host cell" includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this invention.

As known in the art, the term "Fc region" is used to define a C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is that of the EU index as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin generally comprises two constant regions, CH2 and CH3.

As used in the art, "Fc receptor" and "FcR" describe a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc.gamma.RI, Fc.gamma.RII, and Fc.gamma.RIII subclasses, including allelic variants and alternatively spliced forms of these receptors. Fc.gamma.RII receptors include Fc.gamma.RIIA (an "activating receptor") and Fc.gamma.RIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. FcRs are reviewed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92, 1991; Capel et al., Immunomethods, 4:25-34, 1994; and de Haas et al., J. Lab. Clin. Med., 126:330-41, 1995. "FcR" also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol., 117:587, 1976; and Kim et al., J. Immunol., 24:249, 1994).

The term "compete", as used herein with regard to an antibody, means that a first antibody, or an antigen binding fragment (or portion) thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen binding portion thereof, such that the result of binding of the first antibody with its cognate epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. The alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody, can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope. However, where each antibody detectably inhibits the binding of the other antibody with its cognate epitope or ligand, whether to the same, greater, or lesser extent, the antibodies are said to "cross-compete" with each other for binding of their respective epitope(s). Both competing and cross-competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing and/or cross-competing antibodies are encompassed and can be useful for the methods disclosed herein.

A "functional Fc region" possesses at least one effector function of a native sequence Fc region. Exemplary "effector functions" include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity; phagocytosis; down-regulation of cell surface receptors (e.g. B cell receptor), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.

A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. A "variant Fc region" comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native sequence Fc region. In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% sequence identity with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably, at least about 90% sequence identity therewith, more preferably, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith.

The term "effector function" refers to the biological activities attributable to the Fc region of an antibody. Examples of antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), Fc receptor binding, complement dependent cytotoxicity (CDC), phagocytosis, C1q binding, and down regulation of cell surface receptors (e.g., B cell receptor; BCR). See, e.g., U.S. Pat. No. 6,737,056. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions. An exemplary measurement of effector function is through Fc.gamma.3 and/or C1q binding.

As used herein "antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g. natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC activity of a molecule of interest can be assessed using an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., 1998, PNAS (USA), 95:652-656.

"Complement dependent cytotoxicity" or "CDC" refers to the lysing of a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g. an antibody) complexed with a cognate antigen. To assess complement activation, a CDC assay, e.g. as described in Gazzano-Santoro et al., J. Immunol. Methods, 202: 163 (1996), may be performed.

As used herein, "treatment" is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cells, inhibiting metastasis of neoplastic cells, remission of a BCMA associated disease (e.g., cancer or autoimmune disease), decreasing symptoms resulting from a BCMA associated disease (e.g., cancer or autoimmune disease), increasing the quality of life of those suffering from a BCMA associated disease (e.g., cancer or autoimmune disease), decreasing the dose of other medications required to treat a BCMA associated disease (e.g., cancer or autoimmune disease), delaying the progression of a BCMA associated disease (e.g., cancer or autoimmune disease), curing a BCMA associated disease (e.g., cancer or autoimmune disease), and/or prolong survival of patients having a BCMA associated disease (e.g., cancer or autoimmune disease).

"Ameliorating" means a lessening or improvement of one or more symptoms as compared to not administering a BCMA antibody or a BCMA antibody conjugate. "Ameliorating" also includes shortening or reduction in duration of a symptom.

As used herein, an "effective dosage" or "effective amount" of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing incidence or amelioration of one or more symptoms of various BCMA associated diseases or conditions (such as multiple myeloma), decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and/or delaying the progression of the BCMA associated disease of patients. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

An "individual" or a "subject" is a mammal, more preferably, a human. Mammals also include, but are not limited to, farm animals, sport animals, pets, primates, horses, dogs, cats, mice and rats.

As used herein, "vector" means a construct, which is capable of delivering, and, preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

As used herein, "expression control sequence" means a nucleic acid sequence that directs transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence to be transcribed.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005).

The term "acyl donor glutamine-containing tag" or "glutamine tag" as used herein refers to a polypeptide or a protein containing one or more Gin residue(s) that acts as a transglutaminase amine acceptor. See, e.g., WO2012059882 and WO2015015448.

The term "k.sub.on" or "k.sub.a", as used herein, refers to the rate constant for association of an antibody to an antigen. Specifically, the rate constants (k.sub.on/k.sub.a and k.sub.off/k.sub.d) and equilibrium dissociation constants are measured using whole antibody (i.e. bivalent) and monomeric BCMA proteins.

The term "k.sub.off" or "k.sub.d", as used herein, refers to the rate constant for dissociation of an antibody from the antibody/antigen complex.

The term "K.sub.D", as used herein, refers to the equilibrium dissociation constant of an antibody-antigen interaction.

Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X." Numeric ranges are inclusive of the numbers defining the range.

It is understood that wherever embodiments are described herein with the language "comprising," otherwise analogous embodiments described in terms of "consisting of" and/or "consisting essentially of" are also provided.

Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

BCMA Antibodies and Methods of Making Thereof

The present invention provides an antibody that binds to BCMA (e.g., human BCMA (e.g., SEQ ID NO: 353 or accession number: Q02223-2) and characterized by any one or more of the following characteristics: (a) treat, prevent, ameliorate one or more symptoms of a condition associated with malignant cells expressing BCMA in a subject (e.g., B-cell related cancer such as multiple myeloma); (b) inhibit tumor growth or progression in a subject (who has a malignant tumor expressing BCMA); (c) inhibit metastasis of cancer (malignant) cells expressing BCMA in a subject (who has one or more malignant cells expressing BCMA); (f) induce regression (e.g., long-term regression) of a tumor expressing BCMA; (d) exert cytotoxic activity in malignant cells expressing BCMA; and (e) block BCMA interaction with other yet to be identified factors.

In one aspect, provided is an isolated antibody, or an antigen binding fragment thereof, which specifically binds to B-Cell Maturation Antigen (BCMA), wherein the antibody comprises (a) a heavy chain variable (VH) region comprising (i) a VH complementary determining region one (CDR1) comprising the sequence SYX.sub.1MX.sub.2, wherein X.sub.1 is A or P; and X.sub.2 is T, N, or S (SEQ ID NO: 301), GFTFX.sub.1SY, wherein X.sub.1 is G or S (SEQ ID NO: 302), or GFTFX.sub.1SYX.sub.2MX.sub.3, wherein X.sub.1 is G or S, X.sub.2 is A or P; and X.sub.3 is T, N, or S (SEQ ID NO: 303); (ii) a VH CDR2 comprising the sequence AX.sub.1X.sub.2X.sub.3X.sub.4GX.sub.5X.sub.6X.sub.7X.sub.8YADX.sub.9X.sub- .10KG, wherein X.sub.1 is I, V, T, H, L, A, or C; X.sub.2 is S, D, G, T, I, L, F, M, or V; X.sub.3 is G, Y, L, H, D, A, S, or M; X.sub.4 is S, Q, T, A, F, or W; X.sub.5 is G or T; X.sub.6 is N, S, P, Y, W, or F; X.sub.7 is S, T, I, L, T, A, R, V, K, G, or C; X.sub.8 is F, Y, P, W, H, or G; X.sub.9 is V, R, or L; and X.sub.10 is G or T (SEQ ID NO: 305), or X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6, wherein X.sub.1 is S, V, I, D, G, T, L, F, or M; X.sub.2 is G, Y, L, H, D, A, S, or M; X.sub.3 is S, G, F, or W; X.sub.4 is G or S; X.sub.5 is G or T; and X.sub.6 is N, S, P, Y, or W (SEQ ID NO: 306); and iii) a VH CDR3 comprising the sequence VSPIX.sub.1X.sub.2X.sub.3X.sub.4, wherein X.sub.1 is A or Y; X.sub.2 is A or S; and X.sub.3 is G, Q, L, P, or E (SEQ ID NO: 307), or YWPMX.sub.1X.sub.2, wherein X.sub.1 is D, S, T, or A; and X.sub.2 is I, S, L, P, or D (SEQ ID NO: 308); and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9X.sub.10X.- sub.11X.sub.12, wherein X.sub.1 is R, G, W, A, or C; X.sub.2 is A, P, G, L, C, or S; X.sub.3 is S, G, or R; X.sub.4 is Q, C, E, V, or I; X.sub.5 is S, P, G, A, R, or D; X.sub.6 is V, G, I, or L; X.sub.7 is S, E, D, P, or G; X.sub.8 is S, P, F, A, M, E, V, N, D, or Y; X.sub.9 is I, T, V, E, S, A, M, Q, Y, H, R, or F; X.sub.10 is Y or F; X.sub.11 is L, W, or P; and X.sub.12 is A, S, or G (SEQ ID NO: 309); (ii) a VL CDR2 comprising the sequence X.sub.1ASX.sub.2RAX.sub.3, wherein X.sub.1 is G or D; X.sub.2 is S or I; and X.sub.3 is T or P (SEQ ID NO: 310); and (iii) a VL CDR3 comprising the sequence QQYX.sub.1X.sub.2X.sub.3PX.sub.4T, wherein X.sub.1 is G, Q, E, L, F, A, S, M, K, R, or Y; X.sub.2 is S, R, T, G, V, F, Y, D, A, H, V, E, K, or C; X.sub.3 is W, F, or S; and X.sub.4 is L or I (SEQ ID NO: 311), or QQYX.sub.1X.sub.2X.sub.3PX.sub.4, wherein X.sub.1 is G, Q, E, L, F, A, S, M, R, K, or Y; X.sub.2 is S, R, T, G, R, V, D, A, H, E, K, C, F, or Y; X.sub.3 is W, S, or F; and X.sub.4 is L or I (SEQ ID NO: 312).

In another aspect, provided is an isolated antibody, or an antigen binding fragment thereof, which specifically binds to BCMA, wherein the antibody comprises: a VH region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 112, 125, 127, 313, 314, 363, or 365; and/or a VL region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 80, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315, 316, or 364.

In some embodiments, provided is an antibody having any one of partial light chain sequence as listed in Table 1 and/or any one of partial heavy chain sequence as listed in Table 1.

TABLE-US-00001 TABLE 1 mAb Light Chain Heavy Chain P6E01/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA P6E01 ASQSVSSSYLAVVYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YGSPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 1) VSS (SEQ ID NO: 2) P6E01/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H3.AQ ASQSVSSSYLAVVYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YGSPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 1) VSS (SEQ ID NO: 3) L1.LG EIVLTQSPGTLSLSPGERATLSC EVQLLESGGGLVQPGGSLRLSCA F/L3.KW/ RASQSLGSFYLAWYQQKPGQA ASGFTFGSYAMTWVRQAPGKGLE P6E01 PRLLIYGASSRATGIPDRFSGSG WVSAISGSGGNTFYADSVKGRFTI SGTDFTLTISRLEPEDFAVYYCKH SRDNSKNTLYLQMNSLRAEDTAV YGWPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 4) VSS (SEQ ID NO: 2) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 5) VSS (SEQ ID NO: 2) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 6) VSS (SEQ ID NO: 2) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARARVSPIAALMDYWGQGTL NO: 4) VTVSS (SEQ ID NO: 7) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AP RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAPMDYWGQGTLVT NO: 4) VSS (SEQ ID NO: 8) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAQMDYWGQGTLVT NO: 4) VSS (SEQ ID NO: 3) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.PY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AP RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAPMDYWGQGTLVT ID NO: 9) VSS (SEQ ID NO: 8) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.PY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 9) VSS (SEQ ID NO: 3) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAALMDYWGQGTLVT ID NO: 10) VSS (SEQ ID NO: 7) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AP RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAPMDYWGQGTLVT ID NO: 10) VSS (SEQ ID NO: 8) L1.LGF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSLGSFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 10) VSS (SEQ ID NO: 3) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAALMDYWGQGTLVT NO: 11) VSS (SEQ ID NO: 7) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AP RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAPMDYWGQGTLVT NO: 11) VSS (SEQ ID NO: 8) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KW/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAQMDYWGQGTLVT NO: 11) VSS (SEQ ID NO: 3) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.PY/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 12) VSS (SEQ ID NO: 3) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK(SEQ YYCARVSPIAALMDYWGQGTLVT ID NO: 13) VSS (SEQ ID NO: 7) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AP RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAPMDYWGQGTLVT ID NO: 13) VSS (SEQ ID NO: 8) L1.GDF/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.NY/ ASQSVGDFYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 14) VSS (SEQ ID NO: 3) L3.KW/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA P6E01 ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKHY SRDNSKNTLYLQMNSLRAEDTAV GWPPSFTFGQGTKVEIK (SEQ IDYYCARVSPIASGMDYWGQGTLVT NO: 15) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA P6E01 ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 2) L3.NY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA P6E01 ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YNYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 17) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE P6E01 LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE P6E01 RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.QR ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQRKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK(SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 24) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.DY ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAIDYSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.YQ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISYQGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.LT ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISLTGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.HA ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISHAGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H2.QL ASQSVSSSYLAWYQQKPGQAPRLLI ASGFTFGSYAMTWVRQAPGKGLE YGASSRATGIPDRFSGSGSGTDFT WVSAISGSGGNTFYADQLKGRFTI LTISRLEPEDFAVYYCQHYPYPPSFT SRDNSKNTLYLQMNSLRAEDTAV FGQGTKVEIK (SEQ ID NO: 16) YYCARVSPIASGMDYWGQGTLVT VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA

H3.YA ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIYAGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H3.AE ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAEMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H3.AQ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA H3.TAQ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCTRVSPIAAQMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA P6E01 ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 16) VSS (SEQ ID NO: 2) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QR RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQRKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 24) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.DY RLLIYGASSRATGIPDRFSGSGS WVSAIDYSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.YQ RLLIYGASSRATGIPDRFSGSGS WVSAISYQGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK(SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.LT RLLIYGASSRATGIPDRFSGSGS WVSAISLTGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.HA RLLIYGASSRATGIPDRFSGSGS WVSAISHAGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQLKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.YA RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIYAGMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAEMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PS/ ASQSVSSSYPSWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCTRVSPIAAQMDYWGQGTLVT ID NO: 18) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QR RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQRKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 24) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.DY RLLIYGASSRATGIPDRFSGSGS WVSAIDYSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.YQ RLLIYGASSRATGIPDRFSGSGS WVSAISYQGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.LT RLLIYGASSRATGIPDRFSGSGS WVSAISLTGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.HA RLLIYGASSRATGIPDRFSGSGS WVSAISHAGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQLKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK(SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.YA RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIYAGMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAEMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.AH/ ASQSVSAHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCTRVSPIAAQMDYWGQGTLVT ID NO: 19) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.QR LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADQRKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 24) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.DY LLIYGASSRATGIPDRFSGSGSG WVSAIDYSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.YQ LLIYGASSRATGIPDRFSGSGSG WVSAISYQGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.LT LLIYGASSRATGIPDRFSGSGSG WVSAISLTGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.HA LLIYGASSRATGIPDRFSGSGSG WVSAISHAGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H2.QL LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADQLKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H3.YA LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIYAGMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H3.AE LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAEMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H3.AQ LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAQMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.FF/ ASQSVSSFFLAWYQQKPGQAPR ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ LLIYGASSRATGIPDRFSGSGSG WVSAISGSGGNTFYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQHYP SRDNSKNTLYLQMNSLRAEDTAV YPPSFTFGQGTKVEIK (SEQ ID YYCTRVSPIAAQMDYWGQGTLVT NO: 20) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QR RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQRKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 24)

L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.HA RLLIYGASSRATGIPDRFSGSGS WVSAISHAGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIASGMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAEMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCARVSPIAAQMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L1.PH/ ASQSVSPHYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YPYPPSFTFGQGTKVEIK (SEQ YYCTRVSPIAAQMDYWGQGTLVT ID NO: 21) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QR RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQRKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 24) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.DY RLLIYGASSRATGIPDRFSGSGS WVSAIDYSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.YQ RLLIYGASSRATGIPDRFSGSGS WVSAISYQGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.LT RLLIYGASSRATGIPDRFSGSGS WVSAISLTGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.HA RLLIYGASSRATGIPDRFSGSGS WVSAISHAGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 28) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQLKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.YA RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIYAGMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KY/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKYY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCTRVSPIAAQMDYWGQGTLVT NO: 22) VSS (SEQ ID NO: 32) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.DY RLLIYGASSRATGIPDRFSGSGS WVSAIDYSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 25) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.YQ RLLIYGASSRATGIPDRFSGSGS WVSAISYQGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 26) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.LT RLLIYGASSRATGIPDRFSGSGS WVSAISLTGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 27) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H2.QL RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADQLKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIASGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 29) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.YA RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIYAGMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 30) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AE RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAEMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 31) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.AQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCARVSPIAAQMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 3) L3.PY/ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA L3.KF/ ASQSVSSSYLAWYQQKPGQAP ASGFTFGSYAMTWVRQAPGKGLE H3.TAQ RLLIYGASSRATGIPDRFSGSGS WVSAISGSGGNTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCKFY SRDNSKNTLYLQMNSLRAEDTAV PYPPSFTFGQGTKVEIK (SEQ ID YYCTRVSPIAAQMDYWGQGTLVT NO: 23) VSS (SEQ ID NO: 32) P5A2_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA VHVL ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE RLLMYDASIRATGIPDRFSGSGS WVSAISDSGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YGSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 34) (SEQ ID NO: 33) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSVIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C06 LLMYDASIRATGIPDRFSGSGSG WVSAISDSGGSAWYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV QRWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 36) (SEQ ID NO: 35) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C09 RLLMYDASIRATGIPDRFSGSGS WVSAISDSGGSMWYADSVKGRF GTDFTLTISRLEPEDFAVYYCQQ TISRDNSKNTLYLQMNSLRAEDTA YQSWPLTFGQGTKVEIK (SEQ IDVYYCARYWPMSLWGQGTLVTVS NO: 38) S (SEQ ID NO: 37) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSDIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C16 LLMYDASIRATGIPDRFSGSGSG WVSAISdFGGSTYYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QTWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 40) (SEQ ID NO: 39) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSNLYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C03 RLLMYDASIRATGIPDRFSGSGS WVSAISDSGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQGWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 41) (SEQ ID NO: 33) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSAYYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C01 RLLMYDASIRATGIPDRFSGSGS WVSAITASGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YERWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 43) (SEQ ID NO: 42) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSSLYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C26 LLMYDASIRATGIPDRFSGSGSG WVSAISDSGGSTYYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QVWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 45) (SEQ ID NO: 44) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C25 RLLMYDASIRATGIPDRFSGSGS WVSAISdSGGSRWYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YLDWPLTFGQGTKVEIK (SEQ ID YYCARYWPMTPWGQGTLVTVSS NO: 47) (SEQ ID NO: 46) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C22 RLLMYDASIRATGIPDRFSGSGS WVSAVLdSGGSTYYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQVWPLTFGQGTKVEIK (SEQ ID YYCARYWPMTPWGQGTLVTVSS NO: 49) (SEQ ID NO: 48) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSVIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C19 LLMYDASIRATGIPDRFSGSGSG WVSAISdSGGSRWYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQYL ISRDNSKNTLYLQMNSLRAEDTAV AWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSDWGQGTLVTVSS NO: 51) (SEQ ID NO: 50) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C03 RLLMYDASIRATGIPDRFSGSGS WVSAISdSGGSKWYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YFTWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 53) (SEQ ID NO: 52) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSPVYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C07 LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQYE ISRDNSKNTLYLQMNSLRAEDTAV RWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 55) (SEQ ID NO: 54) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSVEYLAWYQQKPGQAP ASGFTFSSYAMNVVVRQAPGKGLE C23 RLLMYDASIRATGIPDRFSGSGS WVSAISdSGGSGWYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YARWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 57) (SEQ ID NO: 56) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSEIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C18 LLMYDASIRATGIPDRFSGSGSG WVSAVLdSGGSTYYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQYF ISRDNSKNTLYLQMNSLRAEDTAV GWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 59) (SEQ ID NO: 58) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVEMSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C10 RLLMYDASIRATGIPDRFSGSGS WVSAISdSGGSCWYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YAHWPLTFGQGTKVEIK (SEQ ID YYCARYWPMTPWGQGTLVTVSS NO: 61) (SEQ ID NO: 60) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C05 RLLMYDASIRATGIPDRFSGSGS WVSAIFaSGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQRWPLTFGQGTKVEIK (SEQ ID YYCARYWPMTPWGQGTLVTVSS NO: 63) (SEQ ID NO: 62)

A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSAQYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C10 RLLMYDASIRATGIPDRFSGSGS WVSAISqWGGSLPYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQRWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 65) (SEQ ID NO: 64) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSAIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C04 LLMYDASIRATGIPDRFSGSGSG WVSAIMsSGGPLYYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QVWPLTFGQGTKVEIK (SEQ ID YYCARYWPMALWGQGTLVTVSS NO: 67) (SEQ ID NO: 66) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCG EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ PSQSVSSSYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C26 LLMYDASIRATGIPDRFSGSGSG WVSAILmSGGSTYYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 69) (SEQ ID NO: 68) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSSYWAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C13 RLLMYDASIRATGIPDRFSGSGS WVSAISdSGGYRYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YESWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 71) (SEQ ID NO: 70) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ GGQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE C01 RLLMYDASIRATGIPDRFSGSGS WVSAILsSGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 73) (SEQ ID NO: 72) A02_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSFIYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE C08 LLMYDASIRATGIPDRFSGSGSG WVSAILdSGGSTYYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV GSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSPWGQGTLVTVSS NO: 75) (SEQ ID NO: 74) P5C1_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA VHVL ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE LLIYDASSRAPGIPDRFSGSGSG WVSAIGGSGGSTYYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQYS ISRDNSKNTLYLQMNSLRAEDTAV TSPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 77) (SEQ ID NO: 76) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSPEYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE C24 RLLIYDASSRAPGIPDRFSGSGS WVSAIGGSGGSLPYADSVKGRFT GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YSVWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 79) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSAIYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C26 LLIYDASSRAPGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT TDFTLTISRLEPEDFAVYYCQQYS ISRDNSKNTLYLQMNSLRAEDTAV AWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 317) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSSvYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C10 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV TWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 79) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C27 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV RWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 81) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 6nM_ ASQSVSPIYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C20 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV AFPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 82) (SEQ ID NO: 78) C01 _Rd4_ EIVLTQSPGTLSLSPGERATLSC EVQLLESGGGLVQPGGSLRLSCA 6nM_ WLSQSVSSTYLAWYQQKPGQA ASGFTFSSYPMSWVRQAPGKGLE C12 PRLLIYDASSRAPGIPDRFSGSG WVSAIGgSGGWSYYADSVKGRFT SGTDFTLTISRLEPEDFAVYYCQ ISRDNSKNTLYLQMNSLRAEDTAV QYSEWPLTFGQGTKVEIK (SEQ YYCARYWPMDSWGQGTLVTVSS ID NO: 84) (SEQ ID NO: 83) C01 _Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C16 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV SWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 85) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASQSVSSIFLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C09 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV AWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 86) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCA EVQLLESGGGLVQPGGSLRLSCA 6nM_ CSQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C09 LLIYDASSRAPGIPDRFSGSGSG WVSATVgSGGSIGYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV AWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 88) (SEQ ID NO: 87) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASCDVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C03 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV MRSPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 89) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0.6nM_ ASEAVPSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C06 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGTISR TDFTLTISRLEPEDFAVYYCQQYS DNSKNTLYLQMNSLRAEDTAVYY AFPLTFGQGTKVEIK (SEQ ID CARYWPMDSWGQGTLVTVSS NO: 90) (SEQ ID NO: 78) C01_Rd4_ EIVLTQSPGTLSLSPGERATLSCC EVQLLESGGGLVQPGGSLRLSCA 6nM_ SSQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE C04 LLIYDASSRAPGIPDRFSGSGSG WVSAIGgSGGSLPYADSVKGRFTI TDFTLTISRLEPEDFAVYYCQQYS SRDNSKNTLYLQMNSLRAEDTAV AFPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 91) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASVRVSSTYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAISdSGGSRWYADSVKGRFT C22 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV MKWPLTFGQGTKVEIK (SEQ ID YYCTRYWPMDIWGQGTLVTVSS NO: 93) (SEQ ID NO: 92) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSAAYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGgSGGSLPYADSVKGRFTI C21 GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YMCWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 94) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSSYWGWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGgSGGSIHYADSVKGRFTI C10 GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQCWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 96) (SEQ ID NO: 95) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAHIgSGGSTYYADSVKGRFTI C04 TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 98) (SEQ ID NO: 97) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSpYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGgSGGSTYYADSVKGRFTI C25 TDFTLTISRLEPEDFAVYYCQQY SRDNSKNTLYLQMNSLRAEDTAV QSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDPWGQGTLVTVSS NO: 100) (SEQ ID NO: 99) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGgSGGSLPYADSVKGRFTI C21 GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 38) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSPIYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLGYADSVKGRFT C11 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV KAWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 102) (SEQ ID NO: 101) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSYLYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT C20 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV MEWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 103) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSAQYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIFASGGSTYYADSVKGRFTI C09 GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YQAWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 105) (SEQ ID NO: 104) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGGSGTWTYYADSVKGRFT C08 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQKWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 107) (SEQ ID NO: 106) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSAVYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGGSGGSLPYADSVKGRFT C19 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YRAWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 108) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASIAVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT C02 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV MVWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 109) (SEQ ID NO: 78) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ PRQSVSSSYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLMYDASIRATGIPDRFSGSGS WVSALFGSGGSTYYADSVKGRFT C23 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQDWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 111) (SEQ ID NO: 110) COMB EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA 0 Rd4 ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE _0.6n RLLMYDASIRATGIPDRFSGSGS WVSAIGGSGGSLPYADSVKGRFT M C29 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 38) (SEQ ID NO: 112) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT C09 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV QEWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 113) (SEQ ID NO: 112) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSASYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAALGSGGSTYYADSVKGRF C12 GTDFTLTISRLEPEDFAVYYCQQ TISRDNSKNTLYLQMNSLRAEDTA YMSWPLTFGQGTKVEIK (SEQ ID VYYCARYWPMDSWGQGTLVTVS NO: 115) S (SEQ ID NO: 114) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSYMYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLIYDASIRATGIPDRFSGSGSG WVSAIGGSGGSTYYADSVKGRFT C30 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV KSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS

NO: 116) (SEQ ID NO: 76) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSALYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAIGGSGGSLPYADSVKGRFT C14 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YYGWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 117) (SEQ ID NO: 112) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQPISSSYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT C07 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV QGWPLTFGQGTKVEIK (SEQ ID YYCARYWPMADWGQGTLVTVSS NO: 119) (SEQ ID NO: 118) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAISDSGGFVYYADSVKGRFTI C02 GTDFTLTISRLEPEDFAVYYCQQ SRDNSKNTLYLQMNSLRAEDTAV YEFWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 121) (SEQ ID NO: 120) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSTYLAWYQQKPGQAPR ASGFTFSSYAMNWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSTYYADSVKGRFT C05 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV MSWPLTFGQGTKVEIK (SEQ ID YYCARYWPMSLWGQGTLVTVSS NO: 123) (SEQ ID NO: 122) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQGISSTYLAWYQQKPGQAPR ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ LLMYDASIRATGIPDRFSGSGSG WVSAIGGSGGSLPYADSVKGRFT C17 TDFTLTISRLEPEDFAVYYCQQY ISRDNSKNTLYLQMNSLRAEDTAV AYWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDIWGQGTLVTVSS NO: 124) (SEQ ID NO: 112) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMNWVRQAPGKGLE 6nM_ RLLMYDASIRATGIPDRFSGSGS WVSACLDSGGSTYYADSVKGRFT C22 GTDFTLTISRLEPEDFAVYYCQQ ISRDNSKNTLYLQMNSLRAEDTAV YQGWPLTFGQGTKVEIK (SEQ ID YYCARYWPMDSWGQGTLVTVSS NO: 126) (SEQ ID NO: 125) COMBO_ EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA Rd4_ ASQSVSVRYLAWYQQKPGQAP ASGFTFSSYPMSWVRQAPGKGLE 0.6nM_ RLLMYDASIRATGIPDRFSGSGS WVSAALGSGGSTYYADSVKGRF C11 GTDFTLTISRLEPEDFAVYYCQQ TISRDNSKNTLYLQMNSLRAEDTA YGSWPITFGQGTKVEIK (SEQ ID VYYCARYWPMSLWGQGTLVTVS NO: 128) S (SEQ ID NO: 127) Conse EIVLTQSPGTLSLSPGERATLSC EVQLLESGGGLVQPGGSLRLSCA nsus X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9X.sub.- 10X.sub.11X.sub.12WY ASGFTFX.sub.1SYX.sub.2MX.sub.3WVRQAPGKG QQKPGQAPRLLMYX.sub.13ASX.sub.14RAX LEWVSAX.sub.4X.sub.5X.sub.6X.sub.7GX.s- ub.8X.sub.9X.sub.10X.sub.11YAD .sub.15GIPDRFSGSGSGTDFTLTISRLE X.sub.12X.sub.13KGRFTISRDNSKNTLYLQMN PEDFAVYYCX.sub.16X.sub.17YX.sub.18X.sub.19PPSF SLRAEDTAVYYCARVSPIX.sub.14- X.sub.15X.sub.16 TFGQGTKVEIK, wherein X.sub.1 is R, MDYWGQGTLVTVSS, wherein X.sub.1 G, W, A, or C; X.sub.2 is A, P, G, L, C, is G or S, X.sub.2 is A or P; X.sub.3 is T, N, or or S; X.sub.3 is S, G, or R; X.sub.4 is Q, C, S; X.sub.4 is I, V, T, H, L, A, or C; X.sub.5 is S, E, V, or I; X.sub.5 is S, P, G, A, R, or D; D, G, T, I, L, F, M, or V; X.sub.6 is G, Y, X.sub.6 is V, G, I, or L; X.sub.7 is S, E, D, P, L, H, D, A, S, or M; X.sub.7 is S, Q, T, A, or G; X.sub.8 is S, P, F, A, M, E, V, N, F, or W; X.sub.8 is G or T; X.sub.9 is N, S, P, D, or Y; X.sub.9 is I, T, V, E, S, A, M, Q, Y, W, or F; X.sub.10 is S, T, I, L, T, A, R, Y, H, R, or F; X.sub.10 is Y or F; X.sub.11 is V, K, G, or C; X.sub.11 is F, Y, P, W, H, L, W, or P; X.sub.12 is A, S, or G, X.sub.13 is or G; X.sub.12 is V, R, or L; X.sub.13 is G or T; G or D; X.sub.14 is S or I; X.sub.15 is T or P; X.sub.14 is A or Y; X.sub.15 is A or S; and X.sub.16 is X.sub.16 is Q or K; X.sub.17 is H or Y; X.sub.18 is G, Q, L, P, or E (SEQ ID NO: 313); G, N, or P; and X.sub.19 is S, W, or Y or (SEQ ID NO: 315); EVQLLESGGGLVQPGGSLRLSCA or ASGFTFX.sub.1SYX.sub.2MX.sub.3WVRQAPGKG EIVLTQSPGTLSLSPGERATLSC LEWVSAX.sub.4X.sub.5X.sub.6X.sub.7GX.sub.8X.sub.9- X.sub.10X.sub.11YAD X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9X.sub.10X.- sub.11X.sub.12WY X.sub.12X.sub.13KGRFTISRDNSKNTLYLQMN QQKPGQAPRLLMYX.sub.13ASX.sub.14RAX.sub.15 SLRAEDTAVYYCARYWPMX.sub.14X.sub- .15 GIPDRFSGSGSGTDFTLTISRLE WGQGTLVTVSS, wherein X.sub.1 is G PEDFAVYYCQQYX.sub.16X.sub.17X.sub.18PX.sub.19F or S, X.sub.2 is A or P; X.sub.3 is T, N, or S; GQGTKVEIK, wherein X.sub.1 is R, G, X.sub.4 is I, V, T, H, L, A, or C; X.sub.5 is S, D, W, A, or C; X.sub.2 is A, P, G, L, C, or G, T, I, L, F, M, or V; X.sub.6 is G, Y, L, S; X.sub.3 is S, G, or R; X.sub.4 is Q, C, E, H, D, A, S, or M; X.sub.7 is S, Q, T, A, F, V, or I; X.sub.5 is S, L, P, G, A, R, or D; or W; X.sub.8 is G or T; X.sub.9 is N, S, P, Y, X.sub.6 is V, G, or I; X.sub.7 is S, E, D, or P; W, or F; X.sub.10 is S, T, I, L, T, A, R, V, X.sub.8 is S, P, F, A, M, E, V, N, D, or K, G, or C; X.sub.11 is F, Y, P, W, H, or Y; X.sub.9 is I, T, V, E, S, A, M, Q, Y, H, G; X.sub.12 is V, R, or L; X.sub.13 is G or T; or R; X.sub.10 is Y or F; X.sub.11 is L, W, or X.sub.14 is D, S, T, or A; and X.sub.15 is I, S, L, P; X.sub.12 is A, S, or G, X.sub.13 is G or D; P, or D (SEQ ID NO: 314) X.sub.14 is S or I; X.sub.15 is T or P; X.sub.16 is G, Q, E, L, F, A, S, M, R, K, or Y; X.sub.17 is S, R, T, G, R, V, D, A, H, E, K, C, F, or Y; X.sub.18 is W, S, or F; and X.sub.19 is L or I (SEQ ID NO: 316) P4G4 EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA ASQSVSSSYLAWYQQKPGQAP ASGFTFSSYAMSWVRQAPGKGLE RLLIYGASSRAYGIPDRFSGSGS WVSAISASGGSTYYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YGSPPLFTFGQGTKVEIK (SEQ YYCARLSWSGAFDNWGQGTLVT ID NO: 80) VSS (SEQ ID NO: 363) P1A11 EIVLTQSPGTLSLSPGERATLSCR EVQLLESGGGLVQPGGSLRLSCA ASQNVSSSYLAWYQQKPGQAP ASGFTFRSYAMSWVRQAPGKGLE RLLIYGASYRATGIPDRFSGSGS WVSAISGSGGSTFYADSVKGRFTI GTDFTLTISRLEPEDFAVYYCQH SRDNSKNTLYLQMNSLRAEDTAV YGSPPSFTFGQGTKVEIK (SEQ YYCATVGTSGAFGIWGQGTLVTV ID NO: 364) SS (SEQ ID NO: 365)

In Table 1, the underlined sequences are CDR sequences according to Kabat and in bold according to Chothia, except for the following heavy chain CDR2 sequences, in which the Chothia CDR sequences are underlined and the Kabat CDR sequences are in bold: P5A2_VHVL, A02_Rd4_0.6 nM_C06, A02_Rd4_0.6 nM_C09 A02_Rd4_6 nM_C16, A02_Rd4_6 nM_C03, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C26 A02_Rd4_6 nM_C25, A02_Rd4_6 nM_C22, A02_Rd4_6 nM_C19, A02_Rd4_0.6 nM_C03 A02_Rd4_6 nM_C07, A02_Rd4_6 nM_C23, A02_Rd4_0.6 nM_C18, A02_Rd4_6 nM_C10 A02_Rd4_6 nM_C05, A02_Rd4_0.6 nM_C10, A02_Rd4_6 nM_C04, A02_Rd4_0.6 nM_C26 A02_Rd4_0.6 nM_C13, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C08, P5C1_VHVL, C01_Rd4_6 nM_C24, C01_Rd4_6 nM_C26, C01_Rd4_6 nM_C10, C01_Rd4_0.6 nM_C27 C01_Rd4_6 nM_C20, C01_Rd4_6 nM_C12, C01_Rd4_0.6 nM_C16, C01 Rd4_0.6 nM_C09 C01_Rd4_6 nM_C09, C01_Rd4_0.6 nM_C03, C01_Rd4_0.6 nM_C06, C01 Rd4_6 nM_C04 COMBO_Rd4_0.6 nM_C22, COMBO_Rd4_6 nM_C21, COMBO_Rd4_6 nM_C10, COMBO_Rd4_0.6 nM_C04, COMBO_Rd4_6 nM_C25, COMBO_Rd4_0.6 nM_C21, COMBO_Rd4_6 nM_C11, COMBO_Rd4_0.6 nM_C20, COMBO_Rd4_6 nM_C09, COMBO_Rd4_6 nM_C08, COMBO_Rd4_0.6 nM_C19, COMBO_Rd4_0.6 nM_C02, COMBO_Rd4_0.6 nM_C23, COMBO_Rd4_0.6 nM_C29, COMBO_Rd4_0.6 nM_C09, COMBO_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C30, COMBO_Rd4_0.6 nM_C14, COMBO_Rd4_6 nM_C07, COMBO_Rd4_6 nM_C02, COMBO_Rd4_0.6 nM_C05, COMBO_Rd4_0.6 nM_C17, COMBO_Rd4_6 nM_C22, and COMBO_Rd4_0.6 nM_C11.

The invention also provides CDR portions of antibodies to BCMA (including Chothia, Kabat CDRs, and CDR contact regions). Determination of CDR regions is well within the skill of the art. It is understood that in some embodiments, CDRs can be a combination of the Kabat and Chothia CDR (also termed "combined CRs" or "extended CDRs"). In some embodiments, the CDRs are the Kabat CDRs. In other embodiments, the CDRs are the Chothia CDRs. In other words, in embodiments with more than one CDR, the CDRs may be any of Kabat, Chothia, combination CDRs, or combinations thereof. Table 2 provides examples of CDR sequences provided herein.

TABLE-US-00002 TABLE 2 Heavy Chain mAb CDRH1 CDRH2 CDRH3 P6E01 SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) P6E01/P6E01; GFTFGSYAMT L1.LGF/ (SEQ ID NO: 131) L3.KW/P6EO1; (extended) L1.LGF/L3.NY/ P6E01; L1.GDF/L3. NY/P6E01; L3.KW/P6E01; L3.PY/P6E01; L3.NY/P6E01; L3.PY/L1.PS/ P6E01; L3.PY/L1.AH/ P6E01; L3.PY/L1.FF/ P6E01; L3.PY/L1.PH/ P6E01; L3.PY/L3.KY/ P6E01; L3.PY/L3.KF/ P6E01; and L3.PY/P6E01. H3.AQ SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIAAQMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 135) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) P6E01/H3.AQ; GFTFGSYAMT (SEQ L1.LGF/L3.KW/ ID NO: 131) H3.AQ; (extended) L1.LGF/L3.PY/ H3.AQ; L1.LGF/L3.NY/ H3.AQ; L1.GDF/L3.KW/ H3.AQ; L1.GDF/L3.PY/ H3.AQ; L1.GDF/L3.NY/ H3.AQ; L3.PY/H3.AQ; L3.PY/L1.PS/ H3.AQ; L3.PY/L1.AH/ H3.AQ; L3.PY/L1.FF/ H3.AQ; L3.PY/L1.PH/ H3.AQ; and L3.PY/L3.KF/ H3.AQ. H3.AL SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIAALMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 136) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L1.LGF/L3.KW/ GFTFGSYAMT (SEQ H3.AL; ID NO: 131) L1.LGF/L3.NY/ (extended) H3.AL. and L1.GDF/L3.NY/ H3.AL. H3.AP SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIAAPMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 137) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L1.LGF/L3.KW/ GFTFGSYAMT (SEQ H3.AP; ID NO: 131) L1.LGF/L3.PY/ (extended) H3.AP; L1.LGF/L3NY/ H3.AP; L1.GDF/L3.KW/ H3.AP; and L1.GDF/L3NY/ H3.AP. H2.QR SYAMT (SEQ ID NO: AISGSGGNTFYADQRKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 138) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.QR; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H2.QR; (extended) L3.PY/L1.AH/ H2.QR; L3.PY/L1.FF/ H2.QR; L3.PY/L1.PH/ H2.QR; and L3.PY/L3.KY/ H2.QR. H2.DY SYAMT (SEQ ID NO: AIDYSGGNTFYADSVKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 139) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID DYSSGN (SEQ ID NO: 140) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.DY; GFTFGSYAMT (SEQ L3.PY/L1.P ID NO: 131) S/H2.DY; (extended) L3.PY/L1.AH/ H2.DY; L3.PY/L1.FF/ H2.DY; L3.PY/L3.KY/ H2.DY; and L3.PY/L3.KF/ H2.DY. H2.YQ SYAMT (SEQ ID NO: AISYQGGNTFYADSVKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 141) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SYQGGN (SEQ ID NO: 142) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.YQ; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H2.YQ; (extended) L3.PY/L1.AH/ H2.YQ; L3.PY/L1.FF/ H2.YQ; L3.PY/L3.KY/ H2.YQ; and L3.PY/L3.KF/ H2.YQ. H2.LT SYAMT (SEQ ID NO: AISLTGGNTFYADSVKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 143) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SLTGGN (SEQ ID NO: 144) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.LT; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H2.LT; (extended) L3.PY/L1.AH/ H2.LT; L3.PY/L1.FF/ H2.LT; L3.PY/L3.KY/ H2.LT; and L3.PY/L3.KF/ H2.LT. H2.HA SYAMT (SEQ ID NO: AISHAGGNTFYADSVKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 145) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SHAGGN (SEQ ID NO: 146) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.HA; GFTFGSYAMT (SEQ L3.PY/L1.AH/ ID NO: 131) H2.HA; (extended) L3.PY/L1.FF/ H2.HA; L3.PY/L1.PH/ H2.HA; and L3.PY/L3.KY/ H2.HA. H2.QL SYAMT (SEQ ID NO: AISGSGGNTFYADQLKG VSPIASGMDY For the 129) (Kabat); (SEQ ID NO: 147) (Kabat) (SEQ ID NO: 134) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H2.QL; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H2.QL; (extended) L3.PY/L1.AH/ H2.QL; L3.PY/L1.FF/ H2.QL; L3.PY/L3.KY/ H2.QL; and L3.PY/L3.KF/ H2.QL. H3.YA SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIYAGMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 148) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H3.YA; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H3.YA; (extended) L3.PY/L1.AH/ H3.YA; L3.PY/L1.FF/ H3.YA; L3.PY/L3.KY/ H3.YA; and L3.PY/L3.KF/ H3.YA. H3.AE SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIAAEMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 149) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H3.AE; GFTFGSYAMT (SEQ L3.PY/L1.AH/ ID NO:131) H3.AE; (extended) L3.PY/L1.FF/ H3.AE; L3.PY/L1.PH/ H3.AE; and L3.PY/L3.KF/ H3.AE. H3.TAQ SYAMT (SEQ ID NO: AISGSGGNTFYADSVKG VSPIAAQMDY For the 129) (Kabat); (SEQ ID NO: 132) (Kabat) (SEQ ID NO: 135) following GFTFGSY (SEQ ID SGSGGN (SEQ ID NO: 133) mAbs: NO: 130) (Chothia); (Chothia) L3.PY/H3.TAQ; GFTFGSYAMT (SEQ L3.PY/L1.PS/ ID NO: 131) H3.TAQ; (extended) L3.PY/L1.AH/ H3.TAQ; L3.PY/L1.FF/ H3.TAQ; L3.PY/L1.PH/ H3.TAQ; and L3.PY/L3.KF/ H3.TAQ. P5A2_ SYAMN (SEQ ID AISDSGGSTYYADSVKG YWPMDI VHVL and NO: 150) (Kabat); (SEQ ID NO: 153) (Kabat) (SEQ ID NO: 155) A02_Rd4_ GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) 6nM_C03 NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSLPYADSVKG YWPMDI (SEQ

Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 158) (Kabat) ID NO: 155) C17; GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) COMBO_ NO: 151) (Chothia); (Chothia) Rd4_0.6nM_ GFTFSSYPMS (SEQ C14; ID NO: 157) COMBO_ (extended) Rd4_0.6nM_ C29; and COMBO_ Rd4_0.6nM_ C09 C01_Rd4_ SYPMS (SEQ ID NO: AIGGSGGSLPYADSVKG YWPMDS (SEQ 6nM_C04; 156) (Kabat); (SEQ ID NO: 158) (Kabat) ID NO: 161) C01_Rd4_ GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) 0.6nM_ NO: 151) (Chothia); (Chothia) C03; GFTFSSYPMS (SEQ C01_Rd4_ ID NO: 157) 0.6nM_ (extended) C06; COMBO_ Rd4_0.6nM_ C02; COMBO_ Rd4_6nM_ C21; C01_Rd4_ 6nM_C26; COMBO_ Rd4_0.6nM_ C19; C01_Rd4_ 6nM_C24; C01_Rd4_ 6nM_C20; C01_Rd4_ 0.6nM_ C09; COMBO_ Rd4_0.6nM_ C21; C01_Rd4_ 0.6nM_ C04_C27; C01_Rd4_ 0.6nM_ C16; C01_Rd4_ 6nM_C10; COMBO_ Rd4_0.6nM_ C20 P5C1_ SYPMS (SEQ ID NO: AIGGSGGSTYYADSVKG YWPMDS (SEQ VHVL and 156) (Kabat); (SEQ ID NO: 162) (Kabat) ID NO: 161) COMBO_ GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) Rd4_0.6nM_ NO: 151) (Chothia); (Chothia) C30 GFTFSSYPMS (SEQ ID NO: 157) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSAVVYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 163) (Kabat) ID NO: 164) C06 GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSAVVYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 163) (Kabat) ID NO: 164) C09 GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDFGGSTYYADSVKG YWPMDI (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 165) (Kabat) ID NO: 155) C16 GFTFSSY (SEQ ID SDFGGS (SEQ ID NO: 166) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AITASGGSTYYADSVKG YWPMSL (SEQ 6nM_C01 NO: 150) (Kabat); (SEQ ID NO: 167) (Kabat) ID NO: 164) GFTFSSY (SEQ ID TASGGS (SEQ ID NO: 168) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSTYYADSVKG YWPMSL (SEQ 6nM_C26 NO: 150) (Kabat); (SEQ ID NO: 153) (Kabat) ID NO: 164) GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSRWYADSVKG YWPMTP (SEQ 6nM_C25 NO: 150) (Kabat); (SEQ ID NO: 169) (Kabat) ID NO: 170) GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN(SEQ ID AVLDSGGSTYYADSVKG YWPMTP (SEQ 6nM_C22 NO: 150) (Kabat); (SEQ ID NO: 171) (Kabat) ID NO: 170) GFTFSSY (SEQ ID LDSGGS (SEQ ID NO: 172) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSRWYADSVKG YWPMSD (SEQ 6nM_C19 NO: 150) (Kabat); (SEQ ID NO: 169) (Kabat) ID NO: 173) GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSKWYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 174) (Kabat) ID NO: 164) C03 GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AIGGSGGSLPYADSVKG YWPMDS (SEQ 6nM_C07 NO: 150) (Kabat); (SEQ ID NO: 158) (Kabat) ID NO: 161) GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSGWYADSVKG YWPMSL (SEQ 6nM_C23 NO: 150) (Kabat); (SEQ ID NO: 175) ID NO: 164) GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AVLDSGGSTYYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 171) (Kabat) ID NO: 164) C18 GFTFSSY (SEQ ID LDSGGS (SEQ ID NO: 172) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGSCWYADSVKG YWPMTP (SEQ 6nM_C10 NO: 150) (Kabat); (SEQ ID NO: 176) (Kabat) ID NO: 170) GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AIFASGGSTYYADSVKG YWPMTP (SEQ 6nM_C05 NO: 150) (Kabat); (SEQ ID NO: 177) (Kabat) ID NO: 170) GFTFSSY (SEQ ID FASGGS (SEQ ID NO: 178) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISGWGGSLPYADSVKG YWPMDS (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 304) (Kabat) ID NO: 161) C10 GFTFSSY (SEQ ID SGWGGS (SEQ ID NO: 179) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AIMSSGGPLYYADSVKG YWPMAL (SEQ 6nM_C04 NO: 150) (Kabat); (SEQ ID NO: 180) (Kabat) ID NO: 182) GFTFSSY (SEQ ID MSSGGP (SEQ ID NO: 181) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AILMSGGSTYYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 183) (Kabat) ID NO: 164) C26 GFTFSSY (SEQ ID LMSGGS (SEQ ID NO: 184) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AISDSGGYRYYADSVKG YWPMSL (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 185) (Kabat) ID NO: 164) C13 GFTFSSY (SEQ ID SDSGGY (SEQ ID NO: 186) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AILSSGGSTYYADSVKG YWPMDI (SEQ 0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 187) (Kabat) ID NO: 155) C01 GFTFSSY (SEQ ID LSSGGS (SEQ ID NO: 188) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) A02_Rd4_ SYAMN (SEQ ID AILDSGGSTYYADSVKG YWPMSP (SEQ 6nM_C08 NO: 150) (Kabat); (SEQ ID NO: 160) (Kabat) ID NO: 189) GFTFSSY (SEQ ID LDSGGS (SEQ ID NO: 172) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) C01_Rd4_ SYPMS (SEQ ID NO: AIGGSGGWSYYADSVKG YWPMDS (SEQ 6nM_C12 156) (Kabat); (SEQ ID NO: 190) (Kabat) ID NO: 161) GFTFSSY (SEQ ID GGSGGW (SEQ ID NO: NO: 151) (Chothia); 191) (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) C01_Rd4_ SYPMS (SEQ ID NO: ATVGSGGSIGYADSVKG YWPMDS (SEQ 6nM_C09 156) (Kabat); (SEQ ID NO: 192) (Kabat) ID NO: 161) GFTFSSY (SEQ ID VGSGGS (SEQ ID NO: 193) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYAMN (SEQ ID AISDSGGSRWYADSVKG YWPMDI (SEQ Rd4_0.6nM_ NO: 150) (Kabat); (SEQ ID NO: 169) (Kabat) ID NO: 155) C22 GFTFSSY (SEQ ID SDSGGS (SEQ ID NO: 154) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSIHYADSVKG YWPMDS (SEQ Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 194) (Chothia) ID NO: 161) C10 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Kabat) GFTFSSYPMS (SEQ ID NO: 157)

(extended) COMBO_ SYPMS (SEQ ID NO: AHIGSGGSTYYADSVKG YWPMDS (SEQ Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 195) (Kabat) ID NO: 161) C04 GFTFSSY (SEQ ID IGSGGS (SEQ ID NO: 196) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSTYYADSVKG YWPMDP (SEQ Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 162) (Kabat) ID NO: 197) C25 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSLPYADSVKG YWPMDS (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 158) (Kabat) ID NO: 161) C21 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSLGYADSVKG YWPMDS (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 198) (Kabat) ID NO: 161) C11 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIFASGGSTYYADSVKG YWPMDS (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 177) (Kabat) ID NO: 161) C09 GFTFSSY (SEQ ID FASGGS (SEQ ID NO: 178) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGTWTYYADSVKG YWPMDS (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 199) (Kabat) ID NO: 161) C08 GFTFSSY (SEQ ID GGSGTW (SEQ ID NO: 200) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: ALFGSGGSTYYADSVKG YWPMDS (SEQ Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 201) (Kabat) ID NO: 161) C23 GFTFSSY (SEQ ID FGSGGS NO: 151) (Chothia); (SEQ ID NO: 202) (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AALGSGGSTYYADSVKG YWPMDS (SEQ Rd4_0.6nM_ 156) (Kabat); (SEQ ID NO: 203) (Kabat) ID NO: 161) C12 GFTFSSY (SEQ ID LGSGGS (SEQ ID NO: 204) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYPMS (SEQ ID NO: AIGGSGGSLPYADSVKG YWPMAD (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 158) (Kabat) ID NO: 205) C07 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) COMBO_ SYAMN (SEQ ID AISDSGGFVYYADSVKG YWPMDS (SEQ Rd4_6nM_ NO: 150) (Kabat); (SEQ ID NO: 206) (Kabat) ID NO: 161) C02 GFTFSSY (SEQ ID SDSGGF (SEQ ID NO: 207 ) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) COMBO_ SYAMN (SEQ ID AIGGSGGSTYYADSVKG YWPMSL (SEQ Rd4_6nM_ NO: 150) (Kabat); (SEQ ID NO: 162) (Kabat) ID NO: 164) C05 GFTFSSY (SEQ ID GGSGGS (SEQ ID NO: 159) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) COMBO_ SYAMN (SEQ ID ACLDSGGSTYYADSVKG YWPMDS (SEQ Rd4_6nM_ NO: 150) (Kabat); (SEQ ID NO: 208) (Kabat) ID NO: 161) C22 GFTFSSY (SEQ ID LDSGGS (SEQ ID NO: 172 ) NO: 151) (Chothia); (Chothia) GFTFSSYAMN (SEQ ID NO: 152) (extended) COMBO_ SYPMS (SEQ ID NO: AALGSGGSTYYADSVKG YWPMSL (SEQ Rd4_6nM_ 156) (Kabat); (SEQ ID NO: 203) (Kabat) ID NO: 164) C11 GFTFSSY (SEQ ID LGSGGS (SEQ ID NO: 204) NO: 151) (Chothia); (Chothia) GFTFSSYPMS (SEQ ID NO: 157) (extended) Heavy SYX.sub.1MX.sub.2, wherein AX.sub.1X.sub.2X.sub.3X.sub.4GX.sub.5X.sub.6X.sub.7X.sub.8YADX.su- b.9 VSPIX.sub.1X.sub.2X.sub.3MDY, chain X.sub.1 is A or P; and X.sub.2 X.sub.10KG, wherein X.sub.1 is I, V, T, wherein X.sub.1 is A or consensus is T, N, or S (Kabat) H, L, A, or C; X.sub.2 is S, D, G, Y; X.sub.2 is A or S; (SEQ ID NO: 301) T, I, L, F, M, or V; X.sub.3 is G, Y, and X.sub.3 is G, Q, L, GFTFX.sub.1SY, wherein L, H, D, A, S, or M; X.sub.4 is S, P, or E (SEQ ID X.sub.1 is G or S (Chothia) Q, T, A, F, or W; X.sub.5 is G or NO: 307) (SEQ ID NO: 302) T; X.sub.6 is N, S, P, Y, W, or F; YWPMX.sub.1X.sub.2, GFTFX.sub.1SYX.sub.2MX.sub.3, X.sub.7 is S, T, I, L, A, R, V, K, G, wherein X.sub.1 is D, wherein X.sub.1 is G or S, or C; X.sub.8 is F, Y, P, W, H, or S, T, or A; and X.sub.2 X.sub.2 is A or P; and X.sub.3 G; X.sub.9 is V, R, or L; and X.sub.10 is is I, S, L, P, or D is T, N, or S (SEQ ID G or T (Kabat) (SEQ ID (SEQ ID NO: 308) NO: 303) (extended) NO: 305) X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6, wherein X.sub.1 is S, V, I, D, G, T, L, F, or M; X.sub.2 is G, Y, L, H, D, A, S, or M; X.sub.3 is S, G, F, or W; X.sub.4 is G or S; X.sub.5 is G or T; and X.sub.6 is N, S, P, Y, or W (Chothia) (SEQ ID NO: 306) P4G4 SYAMS (SEQ ID NO: SASGGS (SEQ ID NO: 368) LSWSGAFDN 366) (Kabat); (Chothia) (SEQ ID NO: 370) GFTFSSY (SEQ ID AISASGGSTYYADSVKG NO: 151) (Chothia); (SEQ ID NO: 369) GFTFSSYAMS (SEQ (Kabat) ID NO: 367) (extended) P1A11 SYAMS (SEQ ID NO: SGSGGS (SEQ ID NO: 359) VGTSGAFGI 366) (Kabat); (Chothia) (SEQ ID NO: 361) GFTFRSY (SEQ ID AISGSGGSTFYADSVKG NO: 371) (SEQ ID NO: 360) (Kabat) GFTFRSYAMS (SEQ ID NO: 372) Light Chain mAb CDRL1 CDRL2 CDRL3 P6E01 RASQSVSSSYLA GASSRAT (SEQ ID NO: QHYGSPPSFT For the (SEQ ID NO: 209) 210) (SEQ ID NO: 211) following mAbs: P6E01/P6E01; and P6E01/H3.AQ. L1.LGF/ RASQSLGSFYLA GASSRAT (SEQ ID NO: KHYGWPPSFT L3.KW (SEQ ID NO: 212) 210) (SEQ ID NO: 213) For the following mAbs: L1.LGF/L3.KW/ P6E01; L1.LGF/L3.KW/ H3.AL; L1.LGF/L3.KW/ H3.AP; and L1.LGF/L3.KW/ H3.AQ L1.LGF/ RASQSLGSFYLA GASSRAT (SEQ ID NO: QHYNYPPSFT L3.NY (SEQ ID NO: 212) 210) (SEQ ID NO: 214) For the following mAbs: L1.LGF/L3.NY/ P6E01; L1.LGF/L3.NY/ H3.AL L1.LGF/L3.NY/ H3.AP; and L1.LGF/L3.NY/ H3AQ L1.GDF/ RASQSVGDFYLA GASSRAT (SEQ ID NO: QHYNYPPSFT L3.NY (SEQ ID NO: 215) 210) (SEQ ID NO: 214) For the following mAbs: L1.GDF/L3.NY/ P6E01; L1.GDF/L3.NY/ H3.AL; L1.GDF/L3.NY/ H3.AP; and L1.GDF/L3.NY/ H3.AQ L1.LGF/ RASQSLGSFYLA GASSRAT (SEQ ID NO: QHYPYPPSFT L3.PY (SEQ ID NO: 212) 210) (SEQ ID NO: 216) For the following mAbs: L1.LGF/L3.PY/ H3.AP; and L1.LGF/L3.PY/ H3.AQ L1.GDF/ RASQSVGDFYLA GASSRAT (SEQ ID NO: KHYGWPPSFT L3.KW (SEQ ID NO: 215) 210) (SEQ ID NO: 213) For the following mAbs: L1.GDF/ L3.KW/H3.AL; L1.GDF/ L3.KW/H3.AP; and L1.GDF/ L3.KW/H3.AQ L1.GDF/ RASQSVGDFYLA GASSRAT (SEQ ID NO: QHYPYPPSFT L3.PY/ (SEQ ID NO: 215) 210) (SEQ ID NO: 216) H3.AQ L3.KW/ RASQSVSSSYLA GASSRAT (SEQ ID NO: KHYGWPPSFT P6E01 (SEQ ID NO: 209) 210) (SEQ ID NO: 213) L3.PY RASQSVSSSYLA GASSRAT (SEQ ID NO: QHYPYPPSFT For the (SEQ ID NO: 209) 210) (SEQ ID NO: 216) following mAbs: L3.PY/P6E01; L3.PY/H2.QR; L3.PY/H2.DY; L3.PY/H2.YQ; L3.PY/H2.LT; L3.PY/H2.HA; L3.PY/H2.QL; L3.PY/H3.YA; L3.PY/H3.AE; L3.PY/H3.AQ;

L3.PY/H3.TAQ L3.NY/ RASQSVSSSYLA GASSRAT (SEQ ID NO: QHYNYPPSFT P6E01 (SEQ ID NO: 209) 210) (SEQ ID NO: 214) L3.PY/ RASQSVSSSYPS GASSRAT (SEQ ID NO: QHYPYPPSFT L1.PS (SEQ ID NO: 217) 210) (SEQ ID NO: 216) For the following mAbs: L3.PY/ L1.PS/ P6E01; L3.PY/L1. PS/H2.QR L3.PY/L1. PS/H2.DY; L3.PY/L1. PS/H2.YQL3. PY/L1.PS/ H2.LT; L3.PY/L1. PS/H2.HA; L3.PY/L1. PS/H2.QL; L3.PY/L1. PS/H3.YA; L3.PY/L1. PS/H3.AE; L3.PY/L1. PS/H3.AQ L3.PY/L1. PS/H3.TAQ L3.PY/ RASQSVSAHYLA GASSRAT (SEQ ID NO: QHYPYPPSFT L1.AH (SEQ ID NO: 218) 210) (SEQ ID NO: 216) For the following mAbs: L3.PY/L1. AH/P6E01 L3.PY/L1. AH/H2.QR L3.PY/L1. AH/H2.DY L3.PY/L1. AH/H2.YQ L3.PY/L1. AH/H2.LT; L3.PY/L1. AH/H2.HA L3.PY/L1. AH/H2.QL; L3.PY/L1. AH/H3.YA; L3.PY/L1. AH/H3.AE; L3.PY/L1. AH/H3.AQ L3.PY/L1. AH/H3.TAQ L3.PY/ RASQSVSSFFLA GASSRAT (SEQ ID NO: QHYPYPPSFT L1.FF (SEQ ID NO: 219) 210) (SEQ ID NO: 216) For the following mAbs: L3.PY/L1. FF/P6E01; L3.PY/L1. FF/H2.QR; L3.PY/L1. FF/H2.DY; L3.PY/L1. FF/H2.YQ; L3.PY/L1. FF/H2.LT; L3.PY/L1. FF/H2.HA; L3.PY/L1. FF/H2.QL; L3.PY/L1. FF/H3.YA; L3.PY/L1. FF/H3.AE; L3.PY/L1. FF/H3.AQ; and L3.PY/L1. FF/H3.TAQ L3.PY/ RASQSVSPHYLA GASSRAT (SEQ ID NO: QHYPYPPSFT L1.PH (SEQ ID NO: 219) 210) (SEQ ID NO: 216) For the following mAbs: L3.PY/L1. PH/P6E01 L3.PY/L1. PH/H2.QR L3.PY/L1. PH/H2.HA L3.PY/L1. PH/H3.AE; L3.PY/L1. PH/H3.AQ; and L3.PY/L1. PH/H3.TAQ L3.PY/ RASQSVSSSYLA GASSRAT (SEQ ID NO: KYYPYPPSFT L3.KY (SEQ ID NO: 209) 210) (SEQ ID NO: 220) For the following mAbs: L3.PY/L3. KY/P6E01 L3.PY/L3. KY/H2.QR L3.PY/L3. KY/H2.DY L3.PY/L3. KY/H2.YQ; L3.PY/L3. KY/H2.LT L3.PY/L3. KY/H2.HA; L3.PY/L3. KY/H2.QL; L3.PY/L3. KY/H3.YA; and L3.PY/L3. KY/H3.TAQ L3.PY/ RASQSVSSSYLA GASSRAT (SEQ ID NO: KFYPYPPSFT (SEQ L3.KF (SEQ ID NO: 209) 210) ID NO: 220) For the following mAbs: L3.PY/L3. KF/H2.DY; L3.PY/L3. KF/H2.YQ; L3.PY/L3. KF/H2.LT; L3.PY/L3. KF/H2.QL; L3.PY/L3. KF/H3.YA; L3.PY/L3. KF/H3.AE; L3.PY/L3. KF/H3.AQ; and L3.PY/L3. KF/H3.TAQ P5A2_ RASQSVSSSYLA DASIRAT QQYGSWPLT (SEQ VHVL (SEQ ID NO: 209) (SEQ ID NO: 221) ID NO: 222) A02_Rd4_ RASQSVSVIYLA DASIRAT QQYQRWPLT 0.6nM_ (SEQ ID NO: 223) (SEQ ID NO: 221) (SEQ ID NO: 224) C06 A02_Rd4_ RASQSVSSSYLA DASIRAT QQYGSWPLT 0.6nM_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 225) C09; COMBO_ Rd_0.6nM_ C29; and COMBO_ Rd4_0.6nM_ C21 A02_Rd4_ RASQSVSDIYLA DASIRAT QQYQTWPLT (SEQ 6nM_ (SEQ ID NO: 226) (SEQ ID NO: 221) ID NO: 227) C16 A02_Rd4_ RASQSVSNIYLA DASIRAT QQYQGWPLT 6nM_ (SEQ ID NO: 228) (SEQ ID NO: 221) (SEQ ID NO: 229) C03 A02_Rd4_ RASQSVSAYYLA DASIRAT QQYERWPLT 6nM_ (SEQ ID NO: 230) (SEQ ID NO: 221) (SEQ ID NO: 231) C01 A02_Rd4_ RASQSVSSIYLA DASIRAT QQYQVWPLT 6nM_ (SEQ ID NO: 232) (SEQ ID NO: 221) (SEQ ID NO: 233) C26 A02_Rd4_ RASQSVSSSYLA DASIRAT QQYLAWPLT 6nM_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 234) C25 A02_Rd4_ RASQSVSSSYLA DASIRAT QQYQVWPLT 6nM_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 233) C22 A02_Rd4_ RASQSVSVIYLA DASIRAT QQYLAWPLT 6nM_ (SEQ ID NO: 223) (SEQ ID NO: 221) (SEQ ID NO: 236) C19 A02_Rd4_ RASQSVSSSYLA DASIRAT QQYFTWPLT 0.6nM_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 237) C03 A02_Rd4_ RASQSVSPYYLA DASIRAT QQYERWPLT 6nM_ (SEQ ID NO: 238) (SEQ ID NO: 221) (SEQ ID NO: 231) C07 A02_Rd4_ RASQSVSVEYLA DASIRAT QQYARWPLT 6nM_ (SEQ ID NO: 239) (SEQ ID NO: 221) (SEQ ID NO: 240 ) C23 A02_Rd4_ RASQSVSEIYLA DASIRAT QQYFGWPLT 0.6nM_ (SEQ ID NO: 241) (SEQ ID NO: 221) (SEQ ID NO: 242) C18 A02_Rd4_ RASQSVEMSYLA DASIRAT QQYAHWPLT 6nM_ (SEQ ID NO: 243) (SEQ ID NO: 221) (SEQ ID NO: 244) C10 A02_Rd4_ RASQSVSSTYLA DASIRAT QQYQRWPLT 6nM_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 224) C05 A02_Rd4_ RASQSVSAQYLA DASIRAT QQYQRWPLT 0.6nM_ (SEQ ID NO: 245) (SEQ ID NO: 221) (SEQ ID NO: 224) C10 A02_Rd4_ RASQSVSAIYLA DASIRAT QQYQVWPLT 6nM_ (SEQ ID NO: 235) (SEQ ID NO: 221) (SEQ ID NO: 233) C04 A02_Rd4_ GPSQSVSSSYLA DASIRAT QQYQSWPLT 0.6nM_ (SEQ ID NO: 246) (SEQ ID NO: 221) (SEQ ID NO: 225) C26 A02_Rd4_ RASQSVSSSYWA DASIRAT QQYESWPLT 0.6nM_ (SEQ ID NO: 247) (SEQ ID NO: 221) (SEQ ID NO: 248) C13 A02_Rd4_ RGGQSVSSSYLA DASIRAT QQYQSWPLT 0.6nM_ (SEQ ID NO: 249) (SEQ ID NO: 221) (SEQ ID NO: 225) C01 A02_Rd4_ RASQSVSFIYLA DASIRAT QQYGSWPLT (SEQ 6nM_ (SEQ ID NO: 250) (SEQ ID NO: 221) ID NO: 222) C08

P5C1_ RASQSVSSTYLA DASSRAP QQYSTSPLT VHVL (SEQ ID NO: 251) (SEQ ID NO: 252) (SEQ ID NO: 253) C01 _Rd4_ RASQSVSPEYLA DASSRAP QQYSVWPLT 6nM_ (SEQ ID NO: 254) (SEQ ID NO: 252) (SEQ ID NO: 255) C24 C01_Rd4_ RASQSVSAIYLA DASSRAP QQYSAWPLT 6nM_ (SEQ ID NO: 235) (SEQ ID NO: 252) (SEQ ID NO: 256) C26 C01_Rd4_ RASQSVSSVYLA DASSRAP QQYSTWPLT 6nM_ (SEQ ID NO: 257) (SEQ ID NO: 252) (SEQ ID NO: 258) C10 C01_Rd4_ RASQSVSSTYLA DASSRAP QQYSRWPLT 0.6nM_ (SEQ ID NO: 251) (SEQ ID NO: 252) (SEQ ID NO: 259) C27 C01_Rd4_ RASQSVSPIYLA DASSRAP QQYSAFPLT 6nM_ (SEQ ID NO: 260) (SEQ ID NO: 252) (SEQ ID NO: 261) C20 C01_Rd4_ WLSQSVSSTYLA DASSRAP QQYSEWPLT 6nM_ (SEQ ID NO: 262) (SEQ ID NO: 252) (SEQ ID NO: 263) C12 C01_Rd4_ RASQSVSSTYLA DASSRAP QQYSSWPLT 0.6nM_ (SEQ ID NO: 251) (SEQ ID NO: 252) (SEQ ID NO: 264) C16 C01_Rd4_ RASQSVSSIFLA DASSRAP QQYSAWPLT 0.6nM_ (SEQ ID NO: 265) (SEQ ID NO: 252) (SEQ ID NO: 256) C09 C01_Rd4_ ACSQSVSSTYLA DASSRAP QQYSAWPLT 6nM_ (SEQ ID NO: 266) (SEQ ID NO: 252) (SEQ ID NO: 256) C09 C01_Rd4_ RASCDVSSTYLA DASSRAP QQYMRSPLT 0.6nM_ (SEQ ID NO: 267) (SEQ ID NO: 252) (SEQ ID NO: 268) C03 C01_Rd4_ RASEAVPSTYLA DASSRAP QQYSAFPLT 0.6nM_ (SEQ ID NO: 269) (SEQ ID NO: 252) (SEQ ID NO: 261) C06 C01_Rd4_ CSSQSVSSTYLA DASSRAP QQYSAFPLT 0.6nM_ (SEQ ID NO: 270) (SEQ ID NO: 252) (SEQ ID NO: 261) C04 COMBO_ RASVRVSSTYLA DASIRAT QQYMKWPLT Rd4_ (SEQ ID NO: 271) (SEQ ID NO: 221) (SEQ ID NO: 272) 0.6nM_ C22 COMBO_ RASQSVSAAYLA DASIRAT QQYMCWPLT Rd4_ (SEQ ID NO: 273) (SEQ ID NO: 221) (SEQ ID NO: 274) 6nM_C21 COMBO_ RASQSVSSSYWG DASIRAT QQYQCWPLT Rd4_6nM_ (SEQ ID NO: 275) (SEQ ID NO: 221) (SEQ ID NO: 276) C10 COMBO_ RASQSVSSTYLA DASIRAT QQYQSWPLT Rd4_ (SEQ ID NO: 251) (SEQ ID NO: 221) (SEQ ID NO: 225) 0.6nM_ C04 COMBO_ RASQSVSSPYLA DASIRAT QQYQSWPLT Rd4_6nM_ (SEQ ID NO: 277) (SEQ ID NO: 221) (SEQ ID NO: 225) C25 COMBO_ RASQSVSPIYLA DASIRAT QQYKAWPLT Rd4_ (SEQ ID NO: 260) (SEQ ID NO: 221) (SEQ ID NO: 278) 6nM_C11 COMBO_ RASQSVSYLYLA DASIRAT QQYMEWPLT Rd4_ (SEQ ID NO: 279) (SEQ ID NO: 221) (SEQ ID NO: 280) 0.6nM_ C20 COMBO_ RASQSVSAQYLA DASIRAT QQYQAWPLT Rd4_ (SEQ ID NO: 245) (SEQ ID NO: 221) (SEQ ID NO: 281) 6nM_C09 COMBO_ RASQSVSSSYLA DASIRAT QQYQKWPLT Rd4_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 282) 6nM_C08 COMBO_ RASQSVSAVYLA DASIRAT QQYRAWPLT Rd4_ (SEQ ID NO: 283) (SEQ ID NO: 221) (SEQ ID NO: 284) 0.6nM_ C19 COMBO_ RASIAVSSTYLA DASIRAT QQYMVWPLT Rd4_ (SEQ ID NO: 285) (SEQ ID NO: 221) (SEQ ID NO: 286) 0.6nM_ C02 COMBO_ RPRQSVSSSYLA DASIRAT QQYQDWPLT Rd4_ (SEQ ID NO: 287) (SEQ ID NO: 221) (SEQ ID NO: 288) 0.6nM_ C23 COMBO_ RASQSVSSTYLA DASIRAT QQYQEWPLT Rd4_ (SEQ ID NO: 251) (SEQ ID NO: 221) (SEQ ID NO: 289) 0.6nM_ C09 COMBO_ RASQSVSASYLA DASIRAT QQYMSWPLT Rd4_ (SEQ ID NO: 290) (SEQ ID NO: 221) (SEQ ID NO: 291) 6nM_C12 COMBO_ RASQSVSYMYLA DASIRAT QQYKSWPLT Rd4_ (SEQ ID NO: 292) (SEQ ID NO: 221) (SEQ ID NO: 293) 0.6nM_ C30 COMBO_ RASQSVSAIYLA DASIRAT QQYYGWPLT Rd4_ (SEQ ID NO: 235) (SEQ ID NO: 221) (SEQ ID NO: 294) 0.6nM_ C14 COMBO_ RASQPISSSYLA DASIRAT QQYQGWPLT Rd4_ (SEQ ID NO: 295) (SEQ ID NO: 221) (SEQ ID NO: 229) 6nM_C07 COMBO_ RASQSVSSSYLA DASIRAT QQYEFWPLT Rd4_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 296) 6nM_C02 COMBO_ RASQSVSSTYLA DASIRAT QQYMSWPLT Rd4_ (SEQ ID NO: 251) (SEQ ID NO: 221) (SEQ ID NO: 291) 0.6nM_ C05 COMBO_ RASQGISSTYLA DASIRAT QQYAYWPLT Rd4_ (SEQ ID NO: 297) (SEQ ID NO: 221) (SEQ ID NO: 298) 0.6nM_ C17 COMBO_ RASQSVSSSYLA DASIRAT QQYQGWPLT Rd4_ (SEQ ID NO: 209) (SEQ ID NO: 221) (SEQ ID NO: 229) 6nM_C22 COMBO_ RASQSVSVRYLA DASIRAT QQYGSWPIT Rd4_ (SEQ ID NO: 299) (SEQ ID NO: 221) (SEQ ID NO: 300) 0.6nM_ C11 Light X.sub.1X.sub.2X.sub.3X.sub.4X.sub.5X.sub.6X.sub.7X.sub.8X.sub.9 X.su- b.1ASX.sub.2RAX.sub.3, wherein X.sub.1 X.sub.1X.sub.2YX.sub.3X.sub.4PPSFT, chain X.sub.10X.sub.11X.sub.12, wherein X.sub.1 is G or D; X.sub.2 is S or I; and wherein X.sub.1 is Q or K; consens is R, G, W, A, or C; X.sub.2 X.sub.3 is T or P (SEQ ID NO: X.sub.2 is H or Y; X.sub.3 is G, us is A, P, G, L, C, or S; 310) N, or P; and X.sub.4 is S, X.sub.3 is S, G, or R; X.sub.4 is W, or Y (SEQ ID Q, C, E, V, or I; X.sub.5 is NO: 311) S, P, G, A, R, or D; X.sub.6 QQYX.sub.1X.sub.2X.sub.3PX.sub.4T, is V, G, I, or L; X.sub.7 is S, wherein X.sub.1 is G, Q, E, D, P, or G; X.sub.8 is S, E, L, F, A, S, M, K, P, F, A, M, E, V, N, D, R, or Y; X.sub.2 is S, R, or Y; X.sub.9 is I, T, V, E, F T, G, V, F, Y, D, A, S, A, M, Q, Y, H, or R; H, V, E, K, or C; X.sub.3 X.sub.10 is Y or F; X.sub.11 is L, is W, F, or S; and X.sub.4 W, or P; and X.sub.12 is A, is L or I (SEQ ID S, or G (SEQ ID NO: NO: 312) 309) P4G4 RASQSVSSSYLA GASSRAY (SEQ ID NO: QHYGSPPLFT (SEQ ID NO: 209) 362) (SEQ ID NO: 499) P1A11 RASQNVSSSYLA GASYRAT (SEQ ID NO: QHYGSPPSFT (SEQ ID NO: 500) 501) (SEQ ID NO: 211)

In some embodiments, the present invention provides an antibody that binds to BCMA and competes with the antibody as described herein, including P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6 nM_C06, A02_Rd4_0.6 nM_C09 A02_Rd4_6 nM_C16, A02_Rd4_6 nM_C03, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C26 A02_Rd4_6 nM_C25, A02_Rd4_6 nM_C22, A02_Rd4_6 nM_C19, A02_Rd4_0.6 nM_C03 A02_Rd4_6 nM_C07, A02_Rd4_6 nM_C23, A02_Rd4_0.6 nM_C18, A02_Rd4_6 nM_C10 A02_Rd4_6 nM_C05, A02_Rd4_0.6 nM_C10, A02_Rd4_6 nM_C04, A02_Rd4_0.6 nM_C26 A02_Rd4_0.6 nM_C13, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C08, P5C1_VHVL, C01_Rd4_6 nM_C24, C01_Rd4_6 nM_C26, C01_Rd4_6 nM_C10, C01_Rd4_0.6 nM_C27 C01_Rd4_6 nM_C20, C01_Rd4_6 nM_C12, C01_Rd4_0.6 nM_C16, C01_Rd4_0.6 nM_C09 C01_Rd4_6 nM_C09, C01_Rd4_0.6 nM_C03, C01_Rd4_0.6 nM_C06, C01_Rd4_6 nM_C04 COMBO_Rd4_0.6 nM_C22, COMBO_Rd4_6 nM_C21, COMBO_Rd4_6 nM_C10, COMBO_Rd4_0.6 nM_C04, COMBO_Rd4_6 nM_C25, COMBO_Rd4_0.6 nM_C21, COMBO_Rd4_6 nM_C11, COMBO_Rd4_0.6 nM_C20, COMBO_Rd4_6 nM_C09, COMBO_Rd4_6 nM_C08, COMBO_Rd4_0.6 nM_C19, COMBO_Rd4_0.6 nM_C02, COMBO_Rd4_0.6 nM_C23, COMBO_Rd4_0.6 nM_C29, COMBO_Rd4_0.6 nM_C09, COMBO_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C30, COMBO_Rd4_0.6 nM_C14, COMBO_Rd4_6 nM_C07, COMBO_Rd4_6 nM_C02, COMBO_Rd4_0.6 nM_C05, COMBO_Rd4_0.6 nM_C17, COMBO_Rd4_6 nM_C22, COMBO_Rd4_0.6 nM_C11, COMBO_Rd4_0.6 nM_C29, P4G4, or P1A11.

In some embodiments, the present invention provides an antibody or an antigen binding fragment, which specifically binds to BCMA, wherein the antibody comprises a VH region comprising a sequence shown in SEQ ID NO: 112; and/or a VL region comprising a sequence shown in SEQ ID NO: 38. In some embodiments, the antibody comprises a light chain comprising the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLMYDASIRATG IPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYQSWPLTFGQGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 357) and a heavy chain comprising the sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAIGGSGG SLPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWPMDIWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 358).

In some embodiments, the present invention provides an antibody or an antigen binding fragment, which specifically bind to BCMA, wherein the antibody comprises a VH region comprising a sequence shown in SEQ ID NO: 2, 32, 42, or 78; and/or a VL region comprising a sequence shown in SEQ ID NO: 6, 16, 43, or 85.

In some embodiments, the invention also provides CDR portions of antibodies to BCMA antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that imbue specificity to the antibody for an antigen. In general, CDR contact regions include the residue positions in the CDRs and Vernier zones which are constrained in order to maintain proper loop structure for the antibody to bind a specific antigen. See, e.g., Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. Determination of CDR contact regions is well within the skill of the art.

The binding affinity (K.sub.D) of the BCMA antibody as described herein to BCMA (such as human BCMA (e.g., (SEQ ID NO: 353) can be about 0.002 nM to about 6500 nM. In some embodiments, the binding affinity is about any of 6500 nm, 6000 nm, 5986 nm, 5567 nm, 5500 nm, 4500 nm, 4000 nm, 3500 nm, 3000 nm, 2500 nm, 2134 nm, 2000 nm, 1500 nm, 1000 nm, 750 nm, 500 nm, 400 nm, 300 nm, 250 nm, 200 nM, 193 nM, 100 nM, 90 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 19 nm, 18 nm, 17 nm, 16 nm, 15 nM, 10 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM, or 0.002 nM. In some embodiments, the binding affinity is less than about any of 6500 nm, 6000 nm, 5500 nm, 5000 nm, 4000 nm, 3000 nm, 2000 nm, 1000 nm, 900 nm, 800 nm, 250 nM, 200 nM, 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, or 0.5 nM.

In some embodiments, the invention encompasses compositions, including pharmaceutical compositions, comprising antibodies described herein or made by the methods and having the characteristics described herein. As used herein, compositions comprise one or more antibodies that bind to BCMA, and/or one or more polynucleotides comprising sequences encoding one or more these antibodies. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients including buffers, which are well known in the art.

The invention also provides methods of making any of these antibodies. The antibodies of this invention can be made by procedures known in the art. The polypeptides can be produced by proteolytic or other degradation of the antibodies, by recombinant methods (i.e., single or fusion polypeptides) as described above or by chemical synthesis. Polypeptides of the antibodies, especially shorter polypeptides up to about 50 amino acids, are conveniently made by chemical synthesis. Methods of chemical synthesis are known in the art and are commercially available. For example, an antibody could be produced by an automated polypeptide synthesizer employing the solid phase method. See also, U.S. Pat. Nos. 5,807,715; 4,816,567; and 6,331,415.

The invention also encompasses fusion proteins comprising one or more fragments or regions from the antibodies of this invention. In one embodiment, a fusion polypeptide is provided that comprises at least 10 contiguous amino acids of the variable light chain region shown in SEQ ID NOs: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 80, 315, 36, or 364, and/or at least 10 amino acids of the variable heavy chain region shown in SEQ ID NOs: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 112, 125, 127, 313, 314, 363, or 365. In other embodiments, a fusion polypeptide is provided that comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of the variable light chain region and/or at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of the variable heavy chain region. In another embodiment, the fusion polypeptide comprises a light chain variable region and/or a heavy chain variable region, as shown in any of the sequence pairs selected from among SEQ ID NOs: 1 and 2, 1 and 3, 4 and 2, 5 and 2, 6 and 2, 4 and 7, 4 and 8, 4 and 3, 9 and 8, 9 and 3, 10 and 7, 10 and 8, 10 and 3, 11 and 7, 11 and 8, 11 and 3, 12 and 3, 13 and 7, 13 and 8, 14 and 3, 15 and 2, 16 and 2, 17 and 2, 18 and 2, 19 and 2, 20 and 2, 21 and 2, 22 and 2, 23 and 2, 16 and 24, 16 and 25, 16 and 26, 16 and 27, 16 and 28, 16 and 29, 16 and 30, 16 and 31, 16 and 3, 16 and 32, 16 and 2, 18 and 24, 18 and 25, 18 and 26, 18 and 27, 18 and 28, 18 and 29, 18 and 30, 18 and 31, 18 and 3, 18 and 32, 19 and 24, 19 and 25, 19 and 26, 19 and 27, 19 and 28, 19 and 29, 19 and 30, 19 and 31, 19 and 3, 19 and 32, 20 and 24, 20 and 25, 20 and 26, 20 and 27, 20 and 28, 20 and 29, 20 and 30, 20 and 31, 20 and 3, 20 and 32, 21 and 24, 21 and 28, 21 and 31, 21 and 3, 21 and 32, 22 and 24, 22 and 25, 22 and 26, 22 and 27, 22 and 28, 22 and 29, 22 and 30, 22 and 32, 23 and 25, 23 and 26, 23 and 27, 23 and 29, 23 and 30, 23 and 31, 23 and 3, 23 and 32, 34 and 33, 36 and 35, 38 and 37, 40 and 39, 41 and 33, 43 and 42, 45 and 44, 47 and 46, 49 and 48, 51 and 50, 53 and 52, 55 and 54, 57 and 56, 59 and 58, 61 and 60, 63 and 62, 65 and 64, 67 and 66, 69 and 68, 71 and 70, 73 and 72, 75 and 74, 77 and 76, 79 and 78, 317 and 78, 79 and 78, 81 and 78, 82 and 78, 84 and 83, 85 and 78, 86 and 78, 88 and 87, 89 and 78, 90 and 78, 91 and 78, 93 and 92, 94 and 78, 96 and 95, 98 and 97, 38 and 78, 102 and 101, 103 and 78, 105 and 104, 107 and 106, 108 and 78, 109 and 78, 111 and 110, 38 and 112, 113 and 112, 115 and 114, 116 and 76, 117 and 112, 119 and 118, 121 and 120, 123 and 122, 124 and 112, 126 and 125, 128 and 127, 80 and 363, or 364 and 365. In another embodiment, the fusion polypeptide comprises one or more CDR(s). In still other embodiments, the fusion polypeptide comprises CDR H3 (VH CDR3) and/or CDR L3 (VL CDR3). For purposes of this invention, a fusion protein contains one or more antibodies and another amino acid sequence to which it is not attached in the native molecule, for example, a heterologous sequence or a homologous sequence from another region. Exemplary heterologous sequences include, but are not limited to a "tag" such as a FLAG tag or a 6His tag. Tags are well known in the art.

The invention also provides isolated polynucleotides encoding the antibodies of the invention, and vectors and host cells comprising the polynucleotide.

In one embodiment, a polynucleotide comprises a sequence encoding the heavy chain and/or the light chain variable regions of antibody P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6 nM_C06, A02_Rd4_0.6 nM_C09 A02_Rd4_6 nM_C16, A02_Rd4_6 nM_C03, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C26 A02_Rd4_6 nM_C25, A02_Rd4_6 nM_C22, A02_Rd4_6 nM_C19, A02_Rd4_0.6 nM_C03 A02_Rd4_6 nM_C07, A02_Rd4_6 nM_C23, A02_Rd4_0.6 nM_C18, A02_Rd4_6 nM_C10 A02_Rd4_6 nM_C05, A02_Rd4_0.6 nM_C10, A02_Rd4_6 nM_C04, A02_Rd4_0.6 nM_C26 A02_Rd4_0.6 nM_C13, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C08, P5C1_VHVL, C01_Rd4_6 nM_C24, C01_Rd4_6 nM_C26, C01_Rd4_6 nM_C10, C01_Rd4_0.6 nM_C27 C01_Rd4_6 nM_C20, C01_Rd4_6 nM_C12, C01_Rd4_0.6 nM_C16, C01_Rd4_0.6 nM_C09 C01_Rd4_6 nM_C09, C01_Rd4_0.6 nM_C03, C01_Rd4_0.6 nM_C06, C01_Rd4_6 nM_C04 COMBO_Rd4_0.6 nM_C22, COMBO_Rd4_6 nM_C21, COMBO_Rd4_6 nM_C10, COMBO_Rd4_0.6 nM_C04, COMBO_Rd4_6 nM_C25, COMBO_Rd4_0.6 nM_C21, COMBO_Rd4_6 nM_C11, COMBO_Rd4_0.6 nM_C20, COMBO_Rd4_6 nM_C09, COMBO_Rd4_6 nM_C08, COMBO_Rd4_0.6 nM_C19, COMBO_Rd4_0.6 nM_C02, COMBO_Rd4_0.6 nM_C23, COMBO_Rd4_0.6 nM_C29, COMBO_Rd4_0.6 nM_C09, COMBO_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C30, COMBO_Rd4_0.6 nM_C14, COMBO_Rd4_6 nM_C07, COMBO_Rd4_6 nM_C02, COMBO_Rd4_0.6 nM_C05, COMBO_Rd4_0.6 nM_C17, COMBO_Rd4_6 nM_C22, COMBO_Rd4_0.6 nM_C11, COMBO_Rd4_0.6 nM_C29, P4G4, or P1A11. The sequence encoding the antibody of interest may be maintained in a vector in a host cell and the host cell can then be expanded and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

The invention also encompasses scFv of antibodies of this invention. Single chain variable region fragments are made by linking light and/or heavy chain variable regions by using a short linking peptide (Bird et al., Science 242:423-426, 1988). An example of a linking peptide is (GGGGS).sub.3 (SEQ ID NO: 498), which bridges approximately 3.5 nm between the carboxy terminus of one variable region and the amino terminus of the other variable region. Linkers of other sequences have been designed and used (Bird et al., 1988, supra). Linkers should be short, flexible polypeptides and preferably comprised of less than about 20 amino acid residues. Linkers can in turn be modified for additional functions, such as attachment of drugs or attachment to solid supports. The single chain variants can be produced either recombinantly or synthetically. For synthetic production of scFv, an automated synthesizer can be used. For recombinant production of scFv, a suitable plasmid containing polynucleotide that encodes the scFv can be introduced into a suitable host cell, either eukaryotic, such as yeast, plant, insect or mammalian cells, or prokaryotic, such as E. coli. Polynucleotides encoding the scFv of interest can be made by routine manipulations such as ligation of polynucleotides. The resultant scFv can be isolated using standard protein purification techniques known in the art.

Other forms of single chain antibodies, such as diabodies or minibodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which heavy chain variable (VH) and light chain variable (VL) domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al., Proc. Natl. Acad Sci. USA 90:6444-6448, 1993; Poljak, R. J., et al., Structure 2:1121-1123, 1994). Minibody includes the VL and VH domains of a native antibody fused to the hinge region and CH3 domain of the immunoglobulin molecule. See, e.g., U.S. Pat. No. 5,837,821.

In another aspect, the invention provides compositions (such as a pharmaceutical compositions) comprising any of the polynucleotides of the invention. In some embodiments, the composition comprises an expression vector comprising a polynucleotide encoding any of the antibodies described herein. In still other embodiments, the composition comprises either or both of the polynucleotides shown in SEQ ID NO: 486 and SEQ ID NO: 485 below:

TABLE-US-00003 COMBO_Rd4_0.6nM_C29 heavy chain variable region (SEQ ID NO: 486) GAAGTCCAACTCCTCGAATCCGGTGGCGGCCTTGTCCAGCCTGGAGGTTC CTTGCGCCTGTCATGTGCCGCCAGCGGATTCACCTTCTCGTCCTACCCGA TGTCGTGGGTCCGCCAGGCTCCGGGAAAGGGCCTGGAATGGGTGTCAGCC ATCGGAGGATCGGGGGGCTCCCTGCCCTACGCCGATATCGTGAAGGGAAG GTTCACCATTAGCCGGGACAACTCCAAGAACACTCTGTACCTCCAAATGA ACAGCCTGAGAGCGGAGGACACCGCAGTGTACTATTGCGCCCGGTACTGG CCAATGGACATCTGGGGCCAGGGGACTCTGGTCACCGTCTCCTCA COMBO_Rd4_0.6nM_C29 light chain variable region (SEQ ID NO: 485) GAGATCGTGCTGACTCAGTCCCCTGGAACCCTGTCCCTGTCACCTGGCGA AAGAGCTACCTTGTCCTGTCGCGCATCACAATCCGTGTCGTCGAGCTATC TCGCGTGGTACCAGCAGAAGCCCGGACAGGCCCCAAGGCTGCTTATGTAC GACGCCTCCATCCGGGCCACTGGTATCCCCGACCGCTTCTCGGGCTCCGG AAGCGGCACCGACTTCACCCTGACTATTTCCCGGCTCGAACCGGAGGATT TCGCCGTGTACTACTGCCAACAGTACCAGAGCTGGCCGCTGACGTTTGGG CAGGGGACCAAGGTCGAAATCAAA

In other embodiments, the composition comprises either or both of the polynucleotides shown in SEQ ID NO: 488 and SEQ ID NO: 487 below:

TABLE-US-00004 L3.PY/H3TAQ heavy chain variable region (SEQ ID NO: 488) GAAGTGCAGCTGCTGGAATCTGGCGGAGGACTGGTGCAGCCTGGCGGCTC TCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCGGCAGCTACGCTA TGACCTGGGTGCGCCAGGCCCCTGGCAAAGGACTGGAATGGGTGTCCGCC ATCTCTGGCAGCGGCGGCAATACCTTCTACGCCGAGAGCGTGAAGGGCCG GTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGA ACAGCCTGCGGGCCGAGGACACCGCCGTGTACTATTGTACACGGGTGTCC CCTATCGCCGCGCAGATGGATTATTGGGGCCAGGGCACTCTGGTCACCGT CTCCTCA L3.PY/H3TAQ heavy chain variable region (SEQ ID NO: 487) GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCAGGCGA AAGAGCCACCCTGTCCTGCAGAGCCAGCCAGAGCGTGTCCAGCAGCTACC TGGCCTGGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTAT GGCGCCTCTTCTAGAGCCACCGGCATCCCCGATAGATTCAGCGGCTCTGG CAGCGGCACCGACTTCACCCTGACCATCAGCAGACTGGAACCCGAGGACT TCGCCGTGTACTACTGCCAGCACTACCCTTATCCCCCCAGCTTCACATTT GGCCAGGGCACCAAGGTGGAGATCAAA

In still other embodiments, the composition comprises either or both of the polynucleotides shown in SEQ ID NO: 490 and SEQ ID NO: 489 below:

TABLE-US-00005 A02_Rd4_0.6nM_C01 heavy chain variable region (SEQ ID NO: 490) GAAGTTCAATTATTGGAATCTGGTGGAGGACTGGTGCAGCCTGGCGGCTC TCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTACGCCA TGAACTGGGTGCGCCAGGCCCCTGGTAAAGGTTTGGAATGGGTTTCTGCT ATTACTGCGTCTGGTGGTTCTACTTACTATGCCGATGTGGTTAAGGGTAG ATTCACCATTTCTAGAGACAACTCTAAGAACACCTTGTACTTGCAAATGA ACTCCTTGAGAGCTGAAGATACTGCTGTTTATTACTGTGCTAGATACTGG CCAATGTCGTTGTGGGGTCAAGGTACTCTGGTCACCGTCTCCTCA A02_Rd4_0.6nM_C01 light chain variable region (SEQ ID NO: 489) GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCTGGTGA AAGAGCTACTTTGTCTTGTAGAGCTTCTCAATCCGTTTCCGCGTATTATT TGGCTTGGTATCAACAAAAACCAGGTCAAGCTCCAAGATTATTGATGTAC GATGCTTCTATTAGAGCCACCGGTATTCCAGATAGATTTTCTGGTTCTGG TTCCGGTACTGATTTCACTTTGACTATCTCTAGATTGGAACCAGAAGATT TCGCTGTTTACTACTGTCAACAATATGAGCGTTGGCCATTGACTTTTGGT CAAGGTACAAAGGTTGAAATCAAACGTGAG

In other embodiments, the composition comprises either or both of the polynucleotides shown in SEQ ID NO: 492 and SEQ ID NO: 491 below:

TABLE-US-00006 A02_Rd4_0.6nM_C16 heavy chain variable region (SEQ ID NO: 492) GAAGTTCAATTATTGGAATCTGGTGGAGGACTGGTGCAGCCTGGCGGCTC TCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTACGCCA TGAACTGGGTGCGCCAGGCCCCTGGTAAAGGTTTGGAATGGGTTTCTGCT ATTTCTGATTTTGGTGGTTCTACTTACTATGCCGATATCGTTAAGGGTAG ATTCACCATTTCTAGAGACAACTCTAAGAACACCTTGTACTTGCAAATGA ACTCCTTGAGAGCTGAAGATACTGCTGTTTATTACTGTGCTAGATACTGG CCAATGGATATTTGGGGTCAAGGTACTCTGGTCACCGTCTCCTCA A02_Rd4_0.6nM_C16 light chain variable region (SEQ ID NO: 491) GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCTGGTGA AAGAGCTACTTTGTCTTGTAGAGCTTCTCAATCCGTTTCCGATCTGTATT TGGCTTGGTATCAACAAAAACCAGGTCAAGCTCCAAGATTATTGATGTAC GATGCTTCTATTAGAGCCACCGGTATTCCAGATAGATTTTCTGGTTCTGG TTCCGGTACTGATTTCACTTTGACTATCTCTAGATTGGAACCAGAAGATT TCGCTGTTTACTACTGTCAACAATATCAGACTTGGCCATTGACTTTTGGT CAAGGTACAAAGGTTGAAATCAAACGTGAG.

Expression vectors, and administration of polynucleotide compositions are further described herein.

In another aspect, the invention provides a method of making any of the polynucleotides described herein.

Polynucleotides complementary to any such sequences are also encompassed by the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules.

RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.

Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a portion thereof) or may comprise a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably, at least about 80% identity, yet more preferably, at least about 90% identity, and most preferably, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a portion thereof.

Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Wis.), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M. O., 1978, A model of evolutionary change in proteins--Matrices for detecting distant relationships. In Dayhoff, M. O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.; Higgins, D. G. and Sharp, P. M., 1989, CABIOS 5:151-153; Myers, E. W. and Muller W., 1988, CABIOS 4:11-17; Robinson, E. D., 1971, Comb. Theor. 11:105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.; Wilbur, W. J. and Lipman, D. J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.

Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).

Suitable "moderately stringent conditions" include prewashing in a solution of 5.times.SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50.degree. C.-65.degree. C., 5.times.SSC, overnight; followed by washing twice at 65.degree. C. for 20 minutes with each of 2.times., 0.5.times. and 0.2.times.SSC containing 0.1% SDS.

As used herein, "highly stringent conditions" or "high stringency conditions" are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50.degree. C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times.Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC (sodium chloride/sodium citrate) and 50% formamide at 55.degree. C., followed by a high-stringency wash consisting of 0.1.times.SSC containing EDTA at 55.degree. C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).

The polynucleotides of this invention can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of skill in the art can use the sequences provided herein and a commercial DNA synthesizer to produce a desired DNA sequence.

For preparing polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotide so amplified can be isolated from the host cell by methods well known within the art. See, e.g., Sambrook et al., 1989.

Alternatively, PCR allows reproduction of DNA sequences. PCR technology is well known in the art and is described in U.S. Pat. Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those of skill in the art, as set forth in Sambrook et al., 1989, supra, for example.

Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial vendors such as BioRad, Strategene, and Invitrogen.

Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the invention. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87/04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.

The vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of introducing vectors or polynucleotides will often depend on features of the host cell.

The invention also provides host cells comprising any of the polynucleotides described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, and CHO cells. See also PCT Publication No. WO 87/04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtillis) and yeast (such as S. cerevisae, S. pombe; or K. lactis). Preferably, the host cells express the cDNAs at a level of about 5 fold higher, more preferably, 10 fold higher, even more preferably, 20 fold higher than that of the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening the host cells for a specific binding to BCMA or an BCMA domain (e.g., domains 1-4) is effected by an immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.

Representative materials of the present invention were deposited in the American Type Culture Collection (ATCC) on Apr. 15, 2015. Vector having ATCC Accession No. PTA-122094 is a polynucleotide encoding a humanized BCMA antibody heavy chain variable region, and vector having ATCC Accession No. PTA-122093 is a polynucleotide encoding a humanized BCMA antibody light chain variable region. The deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The deposit will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Pfizer, Inc. and ATCC, which assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 U.S.C. Section 122 and the Commissioner's rules pursuant thereto (including 37 C.F.R. Section 1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.

BCMA Antibody Conjugates

The present invention also provides a conjugate (or immunoconjugate) of the BCMA antibody as described herein, or of the antigen binding fragment thereof, wherein the antibody or the antigen binding fragment is conjugated to an agent (e.g., a cytotoxic agent) for targeted immunotherapy (e.g., antibody-drug conjugates) either directly or indirectly via a linker. For example, a cytotoxic agent can be linked or conjugated to the BCMA antibody or the antigen binding fragment thereof as described herein for targeted local delivery of the cytotoxic agent moiety to tumors (e.g., BCMA expressing tumor).

Methods for conjugating cytotoxic agent or other therapeutic agents to antibodies have been described in various publications. For example, chemical modification can be made in the antibodies either through lysine side chain amines or through cysteine sulfhydryl groups activated by reducing interchain disulfide bonds for the conjugation reaction to occur. See, e.g., Tanaka et al., FEBS Letters 579:2092-2096, 2005, and Gentle et al., Bioconjugate Chem. 15:658-663, 2004. Reactive cysteine residues engineered at specific sites of antibodies for specific drug conjugation with defined stoichiometry have also been described. See, e.g., Junutula et al., Nature Biotechnology, 26:925-932, 2008. Conjugation using an acyl donor glutamine-containing tag or an endogenous glutamine made reactive (i.e., the ability to form a covalent bond as an acyl donor) by polypeptide engineering in the presence of transglutaminase and an amine (e.g., a cytotoxic agent comprising or attached to a reactive amine) is also described in international applications WO2012/059882 and WO2015015448.

In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody (e.g., a carboxyl terminus, an amino terminus, or at another site in the BCMA antibody). In some embodiments, the tag comprises an amino acid glutamine (Q) or an amino acid sequence LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO: 455), GGGLLQGG (SEQ ID NO: 456), GLLQG (SEQ ID NO: 457), LLQ, GSPLAQSHGG (SEQ ID NO: 458), GLLQGGG (SEQ ID NO: 459), GLLQGG (SEQ ID NO: 460), GLLQ (SEQ ID NO: 461), LLQLLQGA (SEQ ID NO: 462), LLQGA (SEQ ID NO: 463), LLQYQGA (SEQ ID NO: 464), LLQGSG (SEQ ID NO: 465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479), LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483), and LLQLQG (SEQ ID NO: 484).

In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises an amino acid sequence GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475) engineered at the light chain carboxyl terminus of the BCMA antibody. In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises an amino acid sequence LLQG (SEQ ID NO: 454) engineered after residue T135 in the heavy chain of the BCMA antibody. In other embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises an amino acid sequence LLQGA (SEQ ID NO: 463) or LLQGPP (SEQ ID NO: 472) engineered at the heavy chain carboxyl terminus of the BCMA antibody and wherein the lysine residue at the heavy chain carboxyl terminus is deleted. In some embodiments, the BCMA antibody or the conjugate as described herein comprises an amino acid substitution at position 297 of the BCMA antibody (EU numbering scheme). For example, the amino acid asparagine (N) can be substituted with glutamine (Q) or alanine (A) at position 297 of the BCMA antibody.

Also provided is an isolated antibody comprising an acyl donor glutamine-containing tag and an amino acid modification at position 222, 340, or 370 of the antibody (EU numbering scheme) wherein the modification is an amino acid deletion, insertion, substitution, mutation, or any combination thereof. Accordingly, in some embodiments, provided is the BCMA antibody or the conjugate as described herein comprising the acyl donor glutamine-containing tag (e.g., Q, LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO: 455), GGGLLQGG (SEQ ID NO: 456), GLLQG (SEQ ID NO: 457), LLQ, GSPLAQSHGG (SEQ ID NO: 458), GLLQGGG (SEQ ID NO: 459), GLLQGG (SEQ ID NO: 460), GLLQ (SEQ ID NO: 461), LLQLLQGA (SEQ ID NO: 462), LLQGA (SEQ ID NO: 463), LLQYQGA (SEQ ID NO: 464), LLQGSG (SEQ ID NO: 465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479), LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483), and LLQLQG (SEQ ID NO: 484)) conjugated at a specific site (e.g., at a carboxyl terminus of the heavy or light chain, residue T135 in the antibody heavy chain, or at another site) of the BCMA antibody and an amino acid modification at position 222, 340, or 370 of the antibody (EU numbering scheme). In some embodiments, the amino acid modification is a substitution from lysine to arginine (e.g., K222R, K340R, or K370R).

In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGPP (SEQ ID NO: 474) engineered at the C-terminus of the BCMA antibody light chain and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme). In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGA (SEQ ID NO: 475) engineered at the C-terminus of the BCMA antibody light chain and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme). In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQGA (SEQ ID NO: 463) engineered at the C-terminus of the BCMA antibody heavy chain and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme), wherein the lysine residue at the heavy chain carboxyl terminus is deleted. In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQG (SEQ ID NO: 454) engineered after residue T135 in the heavy chain of the BCMA antibody and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme).

In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising a glutamine engineered at position 297 or an amino acid substitution at position 297 from asparagine (N) to another amino acid in the BCMA antibody and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme). For example, in some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGPP (SEQ ID NO: 474) engineered at the C-terminus of the BCMA antibody light chain, an amino acid substitution at position 297 of the BCMA antibody from asparagine (N) to glutamine (Q), and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme). In some embodiments, the BCMA antibody or the conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQG (SEQ ID NO: 454) engineered after residue T135 in the heavy chain of the BCMA antibody, an amino acid substitution at position 297 of the BCMA antibody from asparagine (N) to alanine (A), and an amino acid substitution from lysine to arginine at position 222 of the antibody (EU numbering scheme).

The agents that can be conjugated to the BCMA antibodies or the antigen binding fragments of the present invention include, but are not limited to, cytotoxic agents, immunomodulating agents, imaging agents, therapeutic proteins, biopolymers, or oligonucleotides.

Examples of a cytotoxic agent include, but are not limited to, anthracycline, an auristatin, a dolastatin, a combretastatin, a duocarmycin, a pyrrolobenzodiazepine dimer, an indolino-benzodiazepine dimer, an enediyne, a geldanamycin, a maytansine, a puromycin, a taxane, a vinca alkaloid, a camptothecin, a tubulysin, a hemiasterlin, a spliceostatin, a pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof.

The anthracyclines are derived from bacteria Strepomyces and have been used to treat a wide range of cancers, such as leukemias, lymphomas, breast, uterine, ovarian, and lung cancers. Exemplary anthracyclines include, but are not limited to, daunorubicin, doxorubicin (i.e., adriamycin), epirubicin, idarubicin, valrubicin, and mitoxantrone.

Dolastatins and their peptidic analogs and derivatives, auristatins, are highly potent antimitotic agents that have been shown to have anticancer and antifungal activity. See, e.g., U.S. Pat. No. 5,663,149 and Pettit et al., Antimicrob. Agents Chemother. 42:2961-2965, 1998. Exemplary dolastatins and auristatins include, but are not limited to, dolastatin 10, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), MMAD (Monomethyl Auristatin D or monomethyl dolastatin 10), MMAF (Monomethyl Auristatin F or N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine), MMAE (Monomethyl Auristatin E or N-methylvaline-valine-dolaisoleuine-dolaproine-norephedrine), 5-benzoylvaleric acid-AE ester (AEVB), and other novel auristatins (such as the ones described in U.S. Publication No. 2013/0129753). In some embodiments, the auristatin is 0101 (2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-me- thyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrol- idin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide) having the following structure:

##STR00001##

In some embodiments, the auristatin is 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methox- y-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinamide) having the following structure:

##STR00002##

In some embodiments, the auristatin is 0131-OMe (N,2-dimethylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-- 3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-oxopropyl]p- yrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methylL-valinamide) having the following structure:

##STR00003##

In other embodiments, the auristatin is 0131 (2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methox- y-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide) having the following structure:

##STR00004##

In other embodiments, the auristatin is 0121 (2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy-1-o- xo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-- yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide) having the following structure:

##STR00005##

Camptothecin is a cytotoxic quinoline alkaloid which inhibits the enzyme topoisomerase I. Examples of camptothecin and its derivatives include, but are not limited to, topotecan and irinotecan, and their metabolites, such as SN-38.

Combretastatins are natural phenols with vascular disruption properties in tumors. Exemplary combretastatins and their derivatives include, but are not limited to, combretastatin A-4 (CA-4) and ombrabulin.

Duocarmycin and CC-1065 are DNA alkylating agents with cytotoxic potency. See Boger and Johnson, PNAS 92:3642-3649 (1995). Exemplary duocarmycin and CC-1065 include, but are not limited to, (+)-duocarmycin A and (+)-duocarmycin SA, (+)-CC-1065, and the compounds as disclosed in the international application PCT/IB2015/050280 including, but not limited to, N.about.2.about.-acetyl-L-lysyl-L-valyl-N.about.5.about.-carbamoyl-N-- [4-({[(2-{[({(1S)-1-(chloromethyl)-3-[(5-{[(1S)-1-(chloromethyl)-5-(phosph- onooxy)-1,2-dihydro-3H-benzo[e]indol-3-yl]carbonyl}thiophen-2-yl)carbonyl]- -2,3-dihydro-1H-benzo[e]indol-5-yl}oxy)carbonyl](methyl)amino}ethyl)(methy- l)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide having the structure:

##STR00006## N.about.2.about.-acetyl-L-lysyl-L-valyl-N.about.5.about.-carbamoyl-N-[4-(- {[(2-{[({(8S)-8-(chloromethyl)-6-[(3-{[(1S)-1-(chloromethyl)-8-methyl-5-(p- hosphonooxy)-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl}bicyclo[1.1.- 1]p ent-1-yl)carbonyl]-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-yl- }oxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]oxy}methyl)phenyl]-L-o- rnithinamide having the structure:

##STR00007## N.about.2.about.-acetyl-L-lysyl-L-valyl-N.about.5.about.-carbamoyl-N-[4-(- {[(2-{[({(8S)-8-(chloromethyl)-6-[(4-{[(1S)-1-(chloromethyl)-8-methyl-5-(p- hosphonooxy)-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl}pentacyclo[4- .2.0.0.about.2,5.about..0.about.3,8.about..0.about.4,7.about.]oct-1-yl)car- bonyl]-1-methyl-3,6,7,8-tetrahydropyrrololo[3,2-e]indol-4-yl}oxy)carbonyl]- (methyl)amino}ethyl)(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide having the structure:

##STR00008##

Enediynes are a class of anti-tumor bacterial products characterized by either nine- and ten-membered rings or the presence of a cyclic system of conjugated triple-double-triple bonds. Exemplary enediynes include, but are not limited to, calicheamicin, esperamicin, uncialamicin, dynemicin, and their derivatives.

Geldanamycins are benzoquinone ansamycin antibiotic that bind to Hsp90 (Heat Shock Protein 90) and have been used antitumor drugs. Exemplary geldanamycins include, but are not limited to, 17-AAG (17-N-Allylamino-17-Demethoxygeldanamycin) and 17-DMAG (17-Dimethylaminoethylamino-17-demethoxygeldanamycin).

Hemiasterlin and its analogues (e.g., HTI-286) bind to the tubulin, disrupt normal microtubule dynamics, and, at stoichiometric amounts, depolymerize microtubules.

Maytansines or their derivatives maytansinoids inhibit cell proliferation by inhibiting the microtubules formation during mitosis through inhibition of polymerization of tubulin. See Remillard et al., Science 189:1002-1005, 1975. Exemplary maytansines and maytansinoids include, but are not limited to, mertansine (DM1) and its derivatives as well as ansamitocin.

Pyrrolobenzodiazepine dimers (PBDs) and indolino-benzodiazepine dimers (IGNs) are anti-tumor agents that contain one or more immine functional groups, or their equivalents, that bind to duplex DNA. PBD and IGN molecules are based on the natural product athramycin, and interact with DNA in a sequence-selective manner, with a preference for purine-guanine-purine sequences. Exemplary PBDs and their analogs include, but are not limited to, SJG-136.

Spliceostatins and pladienolides are anti-tumor compounds which inhibit splicing and interacts with spliceosome, SF3b. Examples of spliceostatins include, but are not limited to, spliceostatin A, FR901464, and (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazinyl-2-o- xoethyl)-4-hydroxy-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-y- l}-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-5-oxopent-3-en-2-yl acetate having the structure of

##STR00009## Examples of pladienolides include, but are not limited to, Pladienolide B, Pladienolide D, or E7107.

Taxanes are diterpenes that act as anti-tubulin agents or mitotic inhibitors. Exemplary taxanes include, but are not limited to, paclitaxel (e.g., TAXOL.RTM.) and docetaxel (TAXOTERE.RTM.).

Tubulysins are natural products isolated from a strain of myxobacteria that has been shown to depolymerize microtubules and induce mitotic arrest. Exemplary tubulysins include, but are not limited to, tubulysin A, tubulysin B, and tubulysin D.

Vinca alkyloids are also anti-tubulin agents. Exemplary vinca alkyloids include, but are not limited to, vincristine, vinblastine, vindesine, and vinorelbine.

Accordingly, in some embodiments, the cytotoxic agent is selected from the group consisting of MMAD (Monomethyl Auristatin D), 0101 (2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-me- thyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrol- idin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide), 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methox- y-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinamide), 0131 (2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-p- henylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methox- y-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide), 0131-OMe (N,2-dimethylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-- 3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-oxopropyl]p- yrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methylL-valinamide), 0121(2-methyl-L-proly-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy- -1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidi- n-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide), and (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazinyl-2-o- xoethyl)-4-hydroxy-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-y- l}-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-5-oxopent-3-en-2-yl acetate.

In some embodiments, the agent is an immunomodulating agent. Examples of an immunomodulating agent include, but are not limited to, gancyclovier, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolgate mofetil, methotrextrate, glucocorticoid and its analogs, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factor (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, and IL-21), colony stimulating factors (e.g., granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF)), interferons (e.g., interferons-.alpha., -.beta. and -.gamma.), the stem cell growth factor designated "S 1 factor," erythropoietin and thrombopoietin, or a combination thereof.

In some embodiments, the agent moiety is an imaging agent (e.g., a fluorophore or a chelator), such as fluorescein, rhodamine, lanthanide phosphors, and their derivatives thereof, or a radioisotope bound to a chelator. Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa Fluor.RTM. (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,-TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101). Examples of chelators include, but are not limited to, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (deferoxamine), diethylenetriaminepentaacetic acid (DTPA), and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) (BAPTA).

Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa Fluor.RTM. (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,-TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101).

In some embodiments, therapeutic or diagnostic radioisotopes or other labels (e.g., PET or SPECT labels) can be incorporated in the agent for conjugation to the BCMA antibodies or the antigen binding fragments as described herein. Examples of a radioisotope or other labels include, but are not limited to, .sup.3H, .sup.11C, .sup.13N, .sup.14C, .sup.15N, .sup.15O, .sup.35S, .sup.18F, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.76Br, .sup.77Br, .sup.86Y, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.95Ru, .sup.97Ru, .sup.99Tc, .sup.103Ru, .sup.105Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.111Ag, .sup.111In, .sup.113In, .sup.121Te, .sup.122Te, .sup.123I, .sup.124I, .sup.125I, .sup.125Te, .sup.126I, .sup.131I, .sup.131In, .sup.133I, .sup.142Pr, .sup.143Pr, .sup.153Pb, .sup.153Sm, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166H, .sup.167Tm, .sup.168Tm, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.224Ac, or .sup.225Ac.

In some embodiments, the agent is a therapeutic protein including, but is not limited to, a toxin, a hormone, an enzyme, and a growth factor.

Examples of a toxin protein (or polypeptide) include, but are not limited to, dipththeria (e.g., diphtheria A chain), Pseudomonas exotoxin and endotoxin, ricin (e.g., ricin A chain), abrin (e.g., abrin A chain), modeccin (e.g., modeccin A chain), alpha-sarcin, Aleurites fordii proteins, dianthin proteins, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, enomycin, tricothecenes, inhibitor cystine knot (ICK) peptides (e.g., ceratotoxins), and conotoxin (e.g., KIIIA or SmIIIa).

In some embodiments, the agent is a biocompatible polymer. The BCMA antibodies or the antigen binding fragments as described herein can be conjugated to the biocompatible polymer to increase serum half-life and bioactivity, and/or to extend in vivo half-lives. Examples of biocompatible polymers include water-soluble polymer, such as polyethylene glycol (PEG) or its derivatives thereof and zwitterion-containing biocompatible polymers (e.g., a phosphorylcholine containing polymer).

In some embodiments, the agent is an oligonucleotide, such as anti-sense oligonucleotides.

In another aspect, the invention provides a conjugate of the antibody or the antigen binding fragment as described herein, wherein the conjugate comprises the formula: antibody-(acyl donor glutamine-containing tag)-(linker)-(cytotoxic agent), wherein the acyl donor glutamine-containing tag is engineered at a specific site of the antibody or the antigen binding fragment (e.g., at a carboxyl terminus of the heavy or light chain, after residue T135 in the antibody heavy chain, or at an another site), wherein the tag is conjugated to a linker (e.g., a linker containing one or more reactive amines (e.g., primary amine NH.sub.2)), and wherein the linker is conjugated to a cytotoxic agent (e.g., MMAD or other auristatins such as 0101, 0131, or 3377).

Examples of a linker containing one or more reactive amines include, but are not limited to, Ac-Lys-Gly (acetyl-lysine-glycine), aminocaproic acid, Ac-Lys-.beta.-Ala (acetyl-lysine-.beta.-alanine), amino-PEG2 (polyethylene glycol)-C2, amino-PEG3-C2, amino-PEG6-C2 (or amino PEG6-propionyl), Ac-Lys-Val-Cit-PABC (acetyl-lysine-valine-citrulline-p-aminobenzyloxycarbonyl), amino-PEG6-C2-Val-Cit-PABC, aminocaproyl-Val-Cit-PABC, [(3R,5R)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-- Val-Cit-PABC, [(3S,5S)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-- Val-Cit-PABC, putrescine, or Ac-Lys-putrescine.

In some embodiments, the conjugate is 1) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101; 2) antibody-AcLys-VC-PABC-0101 and comprises N297Q; 3) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101 and comprises N297Q; 4) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-0131 and comprises N297A; 5) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-3377 and comprises N297A; 6) antibody-GGLLQGA (SEQ ID NO: 475)-AcLys-VC-PABC-0101. In some embodiments, the acyl donor glutamine-containing tag comprising, e.g., GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475), is engineered at the C-terminus of the light chain of the antibody. In other embodiments, the acyl donor glutamine-containing tag (e.g., LLQGA (SEQ ID NO: 463) or LLQGPP (SEQ ID NO: 472)) is engineered at the C-terminus of the heavy chain of the antibody, wherein the lysine residue at the C-terminus is deleted. In some embodiments, the acyl donor glutamine-containing tag comprising, e.g., LLQG (SEQ ID NO: 454) is engineered after residue T135 in the antibody heavy chain or replaces amino acid residues E294-N297 in the antibody heavy chain. Examples of the antibody include, but are not limited to, P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6 nM_C06, A02_Rd4_0.6 nM_C09 A02_Rd4_6 nM_C16, A02_Rd4_6 nM_C03, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C26 A02_Rd4_6 nM_C25, A02_Rd4_6 nM_C22, A02_Rd4_6 nM_C19, A02_Rd4_0.6 nM_C03 A02_Rd4_6 nM_C07, A02_Rd4_6 nM_C23, A02_Rd4_0.6 nM_C18, A02_Rd4_6 nM_C10 A02_Rd4_6 nM_C05, A02_Rd4_0.6 nM_C10, A02_Rd4_6 nM_C04, A02_Rd4_0.6 nM_C26 A02_Rd4_0.6 nM_C13, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C08, P5C1_VHVL, C01_Rd4_6 nM_C24, C01_Rd4_6 nM_C26, C01_Rd4_6 nM_C10, C01_Rd4_0.6 nM_C27 C01_Rd4_6 nM_C20, C01_Rd4_6 nM_C12, C01_Rd4_0.6 nM_C16, C01_Rd4_0.6 nM_C09 C01_Rd4_6 nM_C09, C01_Rd4_0.6 nM_C03, C01_Rd4_0.6 nM_C06, C01_Rd4_6 nM_C04

COMBO_Rd4_0.6 nM_C22, COMBO_Rd4_6 nM_C21, COMBO_Rd4_6 nM_C10, COMBO_Rd4_0.6 nM_C04, COMBO_Rd4_6 nM_C25, COMBO_Rd4_0.6 nM_C21, COMBO_Rd4_6 nM_C11, COMBO_Rd4_0.6 nM_C20, COMBO_Rd4_6 nM_C09, COMBO_Rd4_6 nM_C08, COMBO_Rd4_0.6 nM_C19, COMBO_Rd4_0.6 nM_C02, COMBO_Rd4_0.6 nM_C23, COMBO_Rd4_0.6 nM_C29, COMBO_Rd4_0.6 nM_C09, COMBO_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C30, COMBO_Rd4_0.6 nM_C14, COMBO_Rd4_6 nM_C07, COMBO_Rd4_6 nM_C02, COMBO_Rd4_0.6 nM_C05, COMBO_Rd4_0.6 nM_C17, COMBO_Rd4_6 nM_C22, COMBO_Rd4_0.6 nM_C11, COMBO_Rd4_0.6 nM_C29, P4G4, or P1A11.

In one variation, the conjugate further comprises an amino acid substitution from lysine to arginine at position 222. Accordingly, for example, the conjugate is 1) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101 and comprises K222R; 2) antibody-AcLys-VC-PABC-0101 and comprises N297Q and K222R; 3) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101 and comprises N297Q and K222R; 4) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-0131 and comprises N297A and K222R; 5) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-3377 and comprises N297A and K222R; and 6) antibody-GGLLQGA (SEQ ID NO: 475)-AcLys-VC-PABC-0101 and comprises K222R. In some embodiments, the acyl donor glutamine-containing tag comprising, e.g., GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475) is engineered at the C-terminus of the light chain of the antibody. In other embodiments, the acyl donor glutamine-containing tag (e.g., LLQGA (SEQ ID NO: 473) or LLQGPP (SEQ ID NO: 472)) is engineered at the C-terminus of the heavy chain of the antibody, wherein the lysine residue at the C-terminus is deleted. In some embodiments, the acyl donor glutamine-containing tag comprising, e.g., LLQG (SEQ ID NO: 454) is engineered after residue T135 in the antibody heavy chain or replaces amino acid residues E294-N297 in the antibody heavy chain. Examples of the antibody include, but are not limited to, P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6 nM_C06, A02_Rd4_0.6 nM_C09 A02_Rd4_6 nM_C16, A02_Rd4_6 nM_C03, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C26 A02_Rd4_6 nM_C25, A02_Rd4_6 nM_C22, A02_Rd4_6 nM_C19, A02_Rd4_0.6 nM_C03 A02_Rd4_6 nM_C07, A02_Rd4_6 nM_C23, A02_Rd4_0.6 nM_C18, A02_Rd4_6 nM_C10 A02_Rd4_6 nM_C05, A02_Rd4_0.6 nM_C10, A02_Rd4_6 nM_C04, A02_Rd4_0.6 nM_C26 A02_Rd4_0.6 nM_C13, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C08, P5C1_VHVL, C01_Rd4_6 nM_C24, C01_Rd4_6 nM_C26, C01_Rd4_6 nM_C10, C01_Rd4_0.6 nM_C27 C01_Rd4_6 nM_C20, C01_Rd4_6 nM_C12, C01_Rd4_0.6 nM_C16, C01_Rd4_0.6 nM_C09 C01_Rd4_6 nM_C09, C01_Rd4_0.6 nM_C03, C01_Rd4_0.6 nM_C06, C01_Rd4_6 nM_C04

COMBO_Rd4_0.6 nM_C22, COMBO_Rd4_6 nM_C21, COMBO_Rd4_6 nM_C10, COMBO_Rd4_0.6 nM_C04, COMBO_Rd4_6 nM_C25, COMBO_Rd4_0.6 nM_C21, COMBO_Rd4_6 nM_C11, COMBO_Rd4_0.6 nM_C20, COMBO_Rd4_6 nM_C09, COMBO_Rd4_6 nM_C08, COMBO_Rd4_0.6 nM_C19, COMBO_Rd4_0.6 nM_C02, COMBO_Rd4_0.6 nM_C23, COMBO_Rd4_0.6 nM_C29, COMBO_Rd4_0.6 nM_C09, COMBO_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C30, COMBO_Rd4_0.6 nM_C14, COMBO_Rd4_6 nM_C07, COMBO_Rd4_6 nM_C02, COMBO_Rd4_0.6 nM_C05, COMBO_Rd4_0.6 nM_C17, COMBO_Rd4_6 nM_C22, COMBO_Rd4_0.6 nM_C11, COMBO_Rd4_0.6 nM_C29, or P4G4, or P1A11.

CD3 Antibodies and Methods of Making Thereof

The present invention further provides an antibody that binds to CD3 (e.g., human CD3 (SEQ ID NO: 502; or accession number: NM_000733.3).

In one aspect, provided is an isolated antibody, or an antigen binding fragment thereof, which specifically binds to CD3, wherein the antibody comprises a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398, or 400; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399.

In another aspect, provided is an isolated antibody, or an antigen binding fragment thereof, which specifically binds to CD3, wherein the VH region comprises (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449, or 450; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, or 440, 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453.

In some embodiments, provided is an antibody having any one of partial light chain sequence as listed in Table 3 and/or any one of partial heavy chain sequence as listed in Table 3.

TABLE-US-00007 TABLE 3 mAb Light Chain Heavy Chain h2B4 DIVMTQSPDSLAVSLGERATINCT EVQLVESGGGLVQPGGSLRLSCA SSQSLFNVRSRKNYLAWYQQKP ASGFTFSDYYMTWVRQAPGKGLE GQPPKLLISWASTRESGVPDRFS WVAFIRNRARGYTSDHNASVKGR GSGSGTDFTLTISSLQAEDVAVY FTISRDNAKNSLYLQMNSLRAEDT YCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 319) VTVSS (SEQ ID NO: 320) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH-wt KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE VL_TK PGQPPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDHNASVKGR SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT YYCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 321) VTVSS (SEQ ID NO: 322) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE hnps PGQPPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDHNPSVKGR VL_TK SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT YYCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 323) VTVSS (SEQ ID NO: 324) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE yaes PGQPPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDYAESVKGR VL_TK SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT YYCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 325) VTVSS (SEQ ID NO: 326) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE yads PGQPPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDYADSVKGR VL_TK SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT YYCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 327) VTVSS (SEQ ID NO: 328) h2B4- DIVMTQSPDSLAVSLGERATINCT EVQLVESGGGLVQPGGSLRLSCA VH- SSQSLFNVRSRKNYLAWYQQKP ASGFTFSDYYMTWVRQAPGKGLE yaps GQPPKLLISWASTRESGVPDRFS WVAFIRNRARGYTSDYAPSVKGR VL_TK GSGSGTDFTLTISSLQAEDVAVY FTISRDNAKNSLYLQMNSLRAEDT YCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 329) VTVSS (SEQ ID NO: 330) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE hnps PGQPPKLLIYWASTRESGVPDRF WVAFIRNRARGYTSDHNPSVKGR VL_TK- SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT S55Y YYCKQSYDLFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 344) VTVSS (SEQ ID NO: 345) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE hnps PGQPPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDHNPSVKGR VL_TK- SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT S105Q YYCKQSYDLFTFGQGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 346) VTVSS (SEQ ID NO: 347) h2B4- DIVMTQSPDSLAVSLGERATINC EVQLVESGGGLVQPGGSLRLSCA VH- KSSQSLFNVRSRKNYLAWYQQK ASGFTFSDYYMTWVRQAPGKGLE hnps PGQPPKLLIYWASTRESGVPDRF WVAFIRNRARGYTSDHNPSVKGR VL_TK- SGSGSGTDFTLTISSLQAEDVAV FTISRDNAKNSLYLQMNSLRAEDT S55Y/ YYCKQSYDLFTFGQGTKLEIK AVYYCARDRPSYYVLDYWGQGTT S105Q (SEQ ID NO: 348) VTVSS (SEQ ID NO: 349) 2B4 DIVMSQSPPSLAVSVGDKVTMSC EVKLVESGGGLVQPGGSLRLSCA TSSQSLFNSRSRKNYLAWYQQK TFGFTFTDYYMTWVRQPPGKALE SGQSPKLLISWASTRESGVPDRF WVAFIRNRARGYTSDHNASVKGR TGSGSGTDFTLTISSVQAEDLAV FTISRDNSQNILYLQMNTLRAEDS YYCKQSYDLFTFGSGTKLEIK ATYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 350) VTVSS (SEQ ID NO: 351) h2B4-11 DIVMTQSPDSLAVSLGERATINCT EVQLVESGGGLVQPGGSLRLSCA SSQSLFNSRSRKNYLAWYQQKP ASGFTFSDYYMTWVRQAPGKGLE GQPPKLLISWASTRESGVPDRFS WVAFIRNRARGYTSDHNASVKGR GSGSGTDFTLTISSLQAEDVAVY FTISRDNAKNSLYLQMNSLRAEDT YCQQSYDTFTFGSGTKLEIK AVYYCARDRPSYYVLDYWGQGTT (SEQ ID NO: 445) VTVSS (SEQ ID NO: 444) 1C10 DIVMSQSPSSLAVSAGEKVTMSC QVQLQQPGSELVRPGASVILSCKA KSSQSLLNSRTRKNYLAWYQQK SGYTFTSYWMHWVRQRPGQGLE PGQSPKLLIYWASTRESGVPDRF WIGNIYSGGDTINYDEKFKNKAILT TGSGSGTDFTLTIDSVQPEDLAV VDTSSSTAYMHLSSLTSEDSAVYY YYCTQSFILRTFGGGTKLEIK CTRDATSRYFFDYWGQGTTVTVS (SEQ ID NO: 352) S (SEQ ID NO: 354) 1A4 DIVMSQSPSSLAVSAGEKVTMSC QVQLQQSGPDLVKPGASVEISCK KSSQSLLNSRTRKNYLAWYQQK ASGYSFTTYYLHWVRQRPGQGLE PGQSPKLLIYWASTRASGVPDRF WIGWIFPGSDNTKYNEKFKGKATL TGSGSGTDFTLTISSVQAEDLAIY TADTSSSTAYMQLSSLTSEDSAVY YCKQSFILRTFGGGTKLEIK (SEQ FCARNRDYYFDYWGQGTTVTVSS ID NO: 355) (SEQ ID NO: 356) 7A3 DIVVSQSPSSLAVSAGEKVIMSC EVQLQQSGAELVRPGALVKLSCK KSSQSLLNSRTRKNYLAWYQLK GSGFNIKDYYIHWVKQRPEQGLE PGQSPKLLIYSASTRESGVPDRF WIGWIDPENGNNKYDPKFQGKASI TGSGSGTDFTLTISSVQTEDLAV TADTSSNIAYLQLSSLTSEDTAVYY YYCMQSFTLRTFGGGTKLEIK CARNDNYAFDYWGQGTTVTVSS (SEQ ID NO: 443) (SEQ ID NO: 442 ) 25A8 QAWTQESALTTSPGEAVTLTCR EVQLVESGGGLVRPEGSLRLSCA SSTGAVTTSNYANWVQEKPDHL ASGFTFNTYAMNWVRQAPGKGLE FTGLIGGTNTRAPGVPARFSGSLI WVGRIRSKINNYATYYAESVKGRF GDKAALTITGAQTEDEAIYFCVL TLSRDDSLSMVYLQMNSLKNEDT WYNNYWVFGGGTKLTVL (SEQ AMYYCVRHETLRSGISWFASWGQ ID NO: 377) GTLVTVSS (SEQ ID NO: 378) 16G7 QAWTQESALTTSPGETVTLTCR EVQLVDSGGGLVQPKGSLKLSCA SSTGAVTTSNYANWVQEKPDHL ASGFTFNTYAMNWVRQAPGKGLE FTGLIGGTNNRAPGVPARFSGSL WVARIRSKSNNYATYYADSVKDR IGDKAALTITGAQTEDEAIYFCAL FTISRDDSQSRLYLQMNNLKTEDT WYSNHWVFGGGTKLTVL (SEQ AMYYCVRHETLRSGISWFANWG ID NO: 379) QGTLVTVSS (SEQ ID NO: 380) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA B5 SSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNYWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 381) TLVTVSS (SEQ ID NO: 382) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA B8 SSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNHWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 383) TLVTVSS (SEQ ID NO: 384) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA B12 ASTGAVTTSNYANWVQQKPGQ ASGFTFSTYAMNWVRQAPGKGLE APRGLIGGTNTRAPGTPARFSGS WVGRIRSKINNYATYYAESVKGRF LLGGKAALTLSGAQPEDEAEYYC TISRDDSKNTLYLQMNSLKTEDTA VLWYNNHWVFGGGTKLTVL VYYCVRHETLRSGISWFASWGQG (SEQ ID NO: 385) TLVTVSS (SEQ ID NO: 386) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA B13 TSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNHWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 387) TLVTVSS (SEQ ID NO: 388) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA C5 SSTGAVTTSNYANWVQQKPGQA ASGFTFNTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNYWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 389) TLVTVSS (SEQ ID NO: 390) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA C8 SSTGAVTTSNYANWVQQKPGQA ASGFTFNTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNHWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 391) TLVTVSS (SEQ ID NO: 392) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA D13 TSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSHINNYATYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNHWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 393) TLVTVSS (SEQ ID NO: 394) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA E13 TSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKYNNYATYYAESVKGR LGGKAALTLSGAQPEDEAEYYCV FTISRDDSKNTLYLQMNSLKTEDT LWYNNHWVFGGGTKLTVL (SEQ AVYYCVRHETLRSGISWFASWGQ ID NO: 395) GTLVTVSS (SEQ ID NO: 396) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA F13 TSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRERSKINNYATYYAESVKGR LGGKAALTLSGAQPEDEAEYYCV FTISRDDSKNTLYLQMNSLKTEDT LWYNNHWVFGGGTKLTVL (SEQ AVYYCVRHETLRSGISWFASWGQ ID NO: 397) GTLVTVSS (SEQ ID NO: 398) h25A8- QAWTQEPSLTVSPGGTVTLTCR EVQLVESGGGLVKPGGSLRLSCA G13 TSTGAVTTSNYANWVQQKPGQA ASGFTFSTYAMNWVRQAPGKGLE PRGLIGGTNTRAPGTPARFSGSL WVGRIRSKINNYKTYYAESVKGRF LGGKAALTLSGAQPEDEAEYYCV TISRDDSKNTLYLQMNSLKTEDTA LWYNNHWVFGGGTKLTVL (SEQ VYYCVRHETLRSGISWFASWGQG ID NO: 399) TLVTVSS (SEQ ID NO: 400)

In Table 3, the underlined sequences are CDR sequences according to Kabat and in bold according to Chothia.

The invention also provides CDR portions of antibodies to CD3 (including Chothia, Kabat CDRs, and CDR contact regions). Determination of CDR regions is well within the skill of the art. It is understood that in some embodiments, CDRs can be a combination of the Kabat and Chothia CDR (also termed "combined CRs" or "extended CDRs"). In some embodiments, the CDRs are the Kabat CDRs. In other embodiments, the CDRs are the Chothia CDRs. In other words, in embodiments with more than one CDR, the CDRs may be any of Kabat, Chothia, combination CDRs, or combinations thereof. Table 4 provides examples of CDR sequences provided herein.

TABLE-US-00008 TABLE 4 Heavy Chain mAb CDRH1 CDRH2 CDRH3 h2B4 DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) GFTFSDY (SEQ ID FIRNRARGYTSDHNASVKG NO: 332)(Chothia); (SEQ ID NO: 334) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-wt 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK GFTFSDY (SEQ ID FIRNRARGYTSDHNASVKG NO: 332)(Chothia); (SEQ ID NO: 334) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-hnps 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK GFTFSDY (SEQ ID FIRNRARGYTSDHNPSVKG NO: 332)(Chothia); (SEQ ID NO: 336) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-yaes 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK GFTFSDY (SEQ ID FIRNRARGYTSDYAESVKG NO: 332)(Chothia); (SEQ ID NO: 337) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-yads 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK GFTFSDY (SEQ ID FIRNRARGYTSDYADSVKG NO: 332)(Chothia); (SEQ ID NO: 338) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-yaps 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK GFTFSDY (SEQ ID FIRNRARGYTSDYAPSVKG NO: 332)(Chothia); (SEQ ID NO: 339) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-hnps 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK- GFTFSDY (SEQ ID FIRNRARGYTSDHNPSVKG S55Y NO: 332)(Chothia); (SEQ ID NO: 336) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-hnps 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK- GFTFSDY (SEQ ID FIRNRARGYTSDHNPSVKG S105Q NO: 332)(Chothia); (SEQ ID NO: 336) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) h2B4- DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY VH-hnps 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) VL_TK- GFTFSDY (SEQ ID FIRNRARGYTSDHNPSVKG S55Y/ NO: 332)(Chothia); (SEQ ID NO: 336) (Kabat) S105Q GFTFSDYYMT (SEQ ID NO: 333) (Extended) 2B4 DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) GFTFTDY (SEQ ID FIRNRARGYTSDHNASVKG NO: 415)(Chothia); (SEQ ID NO: 418) (Kabat) GFTFTDYYMT (SEQ ID NO: 416) (Extended) h2B4-11 DYYMT (SEQ ID NO: RNRARGYT DRPSYYVLDY 331) (Kabat); (SEQ ID NO: 417) (Chothia) (SEQ ID NO: 335) GFTFSDY (SEQ ID FIRNRARGYTSDHNASVKG NO: 332)(Chothia); (SEQ ID NO: 418) (Kabat) GFTFSDYYMT (SEQ ID NO: 333) (Extended) 1C10 SYWMH (SEQ ID NO: YSGGDT DATSRYFFDY 418) (Kabat) (SEQ ID NO: 421) (Chothia) (SEQ ID NO: 423) GYTFTSY (SEQ ID NIYSGGDTINYDEKFKN NO: 419) (Chothia) (SEQ ID NO: 422) (Kabat) GYTFTSYWMH (SEQ ID NO: 420) (Extended) 1A4 TYYLH (SEQ ID NO: FPGSDN (SEQ ID NO: 427) NRDYYFDY 424) (Kabat) (Chothia) (SEQ ID NO: 429) GYSFTTYY (SEQ ID WIFPGSDNTKYNEKFKG NO: 425) (Chothia) (SEQ ID NO: 428) (Kabat) GYSFTTYYLH (SEQ ID NO: 426) (Extended) 7A3 DYYIH (SEQ ID NO: DPENGN (SEQ ID NO: 449) NDNYAFDY 446) (Kabat) (Chothia) (SEQ ID NO: 451) GFNIKDY(SEQ ID WIDPENGNNKYDPKFQG NO: 447) (Chothia) (SEQ ID NO: 450) (Kabat) GFNIKDYYIH (SEQ ID NO: 448) (Extended) 25A8 TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFNTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 402)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFNTYAMN (SEQ ID NO: 403) (Extended) 16G7 TYAMN (SEQ ID NO: RSKSNNYA (SEQ ID NO: HETLRSGISWFA 401) (Kabat); 404) (Chothia) N (SEQ ID NO: GFTFNTY (SEQ ID RIRSKSNNYATYYADSVKD 406) NO: 402)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFNTYAMN (SEQ ID NO: 403) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA B5 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA B8 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA B12 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA B13 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA C5 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFNTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 402)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFNTYAMN (SEQ ID NO: 403) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA C8 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFNTY (SEQ ID RIRSKINNYATYYAESVKG 406) NO: 402)(Chothia); (SEQ ID NO: 405) (Kabat) GFTFNTYAMN (SEQ ID NO: 403) h25A8- TYAMN (SEQ ID NO: RSHINNYA (SEQ ID NO: HETLRSGISWFA D13 401) (Kabat); 409) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSHINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 410) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKYNNYA (SEQ ID NO: HETLRSGISWFA E13 401) (Kabat); 411) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKYNNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 412) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA F13 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RERSKINNYATYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 413) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) h25A8- TYAMN (SEQ ID NO: RSKINNYA (SEQ ID NO: HETLRSGISWFA G13 401) (Kabat); 404) (Chothia) S (SEQ ID NO: GFTFSTY (SEQ ID RIRSKINNYKTYYAESVKG 406) NO: 407)(Chothia); (SEQ ID NO: 414) (Kabat) GFTFSTYAMN (SEQ ID NO: 408) (Extended) Light Chain mAb CDRH1 CDRH2 CDRH3 h2B4 TSSQSLFNVRSRKN WASTRES KQSYDLFT YLA (SEQ ID NO: 341) (SEQ ID NO: 342) (SEQ ID NO: 340) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-wt YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK (SEQ ID NO: 343) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-hnps YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK (SEQ ID NO: 343) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-yaes YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK (SEQ ID NO: 343) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-yads YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK (SEQ ID NO: 343) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-yaps YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK (SEQ ID NO: 343) 2B4 TSSQSLFNSRSRKN WASTRES KQSYDLFT YLA (SEQ ID NO: (SEQ ID NO: 341) (SEQ ID NO: 342) 430) h2B4-11 TSSQSLFNSRSRKN WASTRES QQSYDTFT YLA (SEQ ID NO: (SEQ ID NO: 341) (SEQ ID NO: 446) 430) 1C10 KSSQSLLNSRTRKN WASTRES TQSFILRT (SEQ Y (SEQ ID NO: 431) (SEQ ID NO: 341) ID NO: 432)

1A4 KSSQSLLNSRTRKN WASTRAS KQSFILRT (SEQ Y (SEQ ID NO: 431) (SEQ ID NO: 433) ID NO: 434) 7A3 KSSQSLLNSRTRKN SASTRES MQSFTLRT Y (SEQ ID NO: 431) (SEQ ID NO: 452) (SEQ ID NO: 453) h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-hnps YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK- (SEQ ID NO: 343) S55Y h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-hnps YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK- (SEQ ID NO: 343) S105Q h2B4- KSSQSLFNVRSRKN WASTRES KQSYDLFT VH-hnps YLA (SEQ ID NO: 341) (SEQ ID NO: 342) VL_TK- (SEQ ID NO: 343) S55Y/ S105Q 25A8 RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNYWV (SEQ ID NO: 435) 436) (SEQ ID NO: 437) 16G7 RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: ALWYSNHWV (SEQ ID NO: 435) 436) (SEQ ID NO: 438) h25A8- RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNYWV B5 (SEQ ID NO: 435) 436) (SEQ ID NO: 437) h25A8- RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV B8 (SEQ ID NO: 435) 436) (SEQ ID NO: 439) h25A8- RASTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV B12 (SEQ ID NO: 440) 436) (SEQ ID NO: 439) h25A8- RTSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV B13 (SEQ ID NO: 441) 436) (SEQ ID NO: 439) h25A8- RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNYWV C5 (SEQ ID NO: 435) 436) (SEQ ID NO: 437) h25A8- RSSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV C8 (SEQ ID NO: 435) 436) (SEQ ID NO: 439) h25A8- RTSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV D13 (SEQ ID NO: 441) 436) (SEQ ID NO: 439) h25A8- RTSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV E13 (SEQ ID NO: 441) 436) (SEQ ID NO: 439) h25A8- RTSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV F13 (SEQ ID NO: 441) 436) (SEQ ID NO: 439) h25A8- RTSTGAVTTSNYAN GTNTRAP (SEQ ID NO: VLWYNNHWV G13 (SEQ ID NO: 441) 436) (SEQ ID NO: 439)

The invention also provides isolated polynucleotides encoding the antibodies of the invention, and vectors and host cells comprising the polynucleotide.

In one embodiment, a polynucleotide comprises a sequence encoding the heavy chain and/or the light chain variable regions of antibody h2B4, h2B4-VH-wt VL_TK, h2B4-VH-hnps VL_TK, h2B4-VH-yaes VL_TK, h2B4-VH-yads VL_TK, h2B4-VH-yaps VL_TK, h2B4-VH-hnps VL_TK-S55Y, h2B4-VH-hnps VL_TK-S105Q, h2B4-vH-hnps VL_TK-S55Y/S105Q, 2B4, h2B4-11, 1C10, 1A4, 7A3, 25A8, 16G7, h25A8-B5, h25A8-B8, h25A8-B12, h25A8-B13, h25A8-C5, h25A8-C8, h25A8-D13, h25A8-E13, h25A8-F13, or h25A8-G13. The sequence encoding the antibody of interest may be maintained in a vector in a host cell and the host cell can then be expanded and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

The invention also encompasses fusion proteins comprising one or more fragments or regions from the antibodies of this invention. In one embodiment, a fusion polypeptide is provided that comprises at least 10 contiguous amino acids of the variable light chain region shown in SEQ ID NOs: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 445, 352, 355, 443, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399, and/or at least 10 amino acids of the variable heavy chain region shown in SEQ ID NOs: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 354, 356, 444, 442, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, or 400. In other embodiments, a fusion polypeptide is provided that comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of the variable light chain region and/or at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of the variable heavy chain region. In another embodiment, the fusion polypeptide comprises a light chain variable region and/or a heavy chain variable region, as shown in any of the sequence pairs selected from among SEQ ID NOs: 319 and 320, 321 and 322, 323 and 324, 325 and 326, 327 and 328, 329 and 330, 344 and 345, 346 and 347, 348 and 349, 350 and 351, 445 and 444, 352 and 354, 355 and 356, 443 and 442, 377 and 378, 379 and 380, 381 and 382, 383 and 384, 385 and 386, 387 and 388, 389 and 390, 391 and 392, 393 and 394, 395 and 396, 397 and 398, or 399 and 400. In another embodiment, the fusion polypeptide comprises one or more CDR(s). In still other embodiments, the fusion polypeptide comprises CDR H3 (VH CDR3) and/or CDR L3 (VL CDR3). For purposes of this invention, a fusion protein contains one or more antibodies and another amino acid sequence to which it is not attached in the native molecule, for example, a heterologous sequence or a homologous sequence from another region. Exemplary heterologous sequences include, but are not limited to a "tag" such as a FLAG tag or a 6His tag. Tags are well known in the art.

A fusion polypeptide can be created by methods known in the art, for example, synthetically or recombinantly. Typically, the fusion proteins of this invention are made by preparing an expressing a polynucleotide encoding them using recombinant methods described herein, although they may also be prepared by other means known in the art, including, for example, chemical synthesis.

Representative materials of the CD3 antibody in the present invention were deposited in the American Type Culture Collection (ATCC) on Sep. 11, 2015. Vector having ATCC Accession No. PTA-122513 is a polynucleotide encoding a humanized CD3 antibody heavy chain variable region, and vector having ATCC Accession No. PTA-122512 is a polynucleotide encoding a humanized CD3 antibody light chain variable region. The deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The deposit will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Pfizer, Inc. and ATCC, which assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 U.S.C. Section 122 and the Commissioner's rules pursuant thereto (including 37 C.F.R. Section 1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.

Bispecific Antibodies and Methods of Making

Bispecific antibodies, monoclonal antibodies that have binding specificities for at least two different antigens, can be prepared using the antibodies disclosed herein. Methods for making bispecific antibodies are known in the art (see, e.g., Suresh et al., Methods in Enzymology 121:210, 1986). Traditionally, the recombinant production of bispecific antibodies was based on the coexpression of two immunoglobulin heavy chain-light chain pairs, with the two heavy chains having different specificities (Millstein and Cuello, Nature 305, 537-539, 1983).

According to one approach to making bispecific antibodies, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant region sequences. The fusion preferably is with an immunoglobulin heavy chain constant region, comprising at least part of the hinge, CH2 and CH3 regions. It is preferred to have the first heavy chain constant region (CH1), containing the site necessary for light chain binding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are cotransfected into a suitable host organism. This provides for great flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yields. It is, however, possible to insert the coding sequences for two or all three polypeptide chains in one expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios are of no particular significance.

In one approach, the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure, with an immunoglobulin light chain in only one half of the bispecific molecule, facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations. This approach is described in PCT Publication No. WO 94/04690.

In another approach, the bispecific antibodies are composed of amino acid modification in the first hinge region in one arm, and the substituted/replaced amino acid in the first hinge region has an opposite charge to the corresponding amino acid in the second hinge region in another arm. This approach is described in International Patent Application No. PCT/US2011/036419 (WO2011/143545).

In another approach, the formation of a desired heteromultimeric or heterodimeric protein (e.g., bispecific antibody) is enhanced by altering or engineering an interface between a first and a second immunoglobulin-like Fc region (e.g., a hinge region and/or a CH3 region). In this approach, the bispecific antibodies may be composed of a CH3 region, wherein the CH3 region comprises a first CH3 polypeptide and a second CH3 polypeptide which interact together to form a CH3 interface, wherein one or more amino acids within the CH3 interface destabilize homodimer formation and are not electrostatically unfavorable to homodimer formation. This approach is described in International Patent Application No. PCT/US2011/036419 (WO2011/143545).

In another approach, the bispecific antibodies can be generated using a glutamine-containing peptide tag engineered to the antibody directed to an epitope (e.g., BCMA) in one arm and another peptide tag (e.g., a Lys-containing peptide tag or a reactive endogenous Lys) engineered to a second antibody directed to a second epitope in another arm in the presence of transglutaminase. This approach is described in International Patent Application No. PCT/IB2011/054899 (WO2012/059882).

In another aspect of the invention, the heterodimeric protein (e.g., bispecific antibody) as described herein comprises a full-length human antibody, wherein a first antibody variable domain of the heterodimeric protein is capable of recruiting the activity of a human immune effector cell by specifically binding to an effector antigen located on the human immune effector cell, and wherein a second antibody variable domain of the heterodimeric protein is capable of specifically binding to a target antigen. In some embodiments, the human antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the heterodimeric protein comprises an immunologically inert Fc region.

The human immune effector cell can be any of a variety of immune effector cells known in the art. For example, the immune effector cell can be a member of the human lymphoid cell lineage, including, but not limited to, a T cell (e.g., a cytotoxic T cell), a B cell, and a natural killer (NK) cell. The immune effector cell can also be, for example without limitation, a member of the human myeloid lineage, including, but not limited to, a monocyte, a neutrophilic granulocyte, and a dendritic cell. Such immune effector cells may have either a cytotoxic or an apoptotic effect on a target cell or other desired effect upon activation by binding of an effector antigen.

The effector antigen is an antigen (e.g., a protein or a polypeptide) that is expressed on the human immune effector cell. Examples of effector antigens that can be bound by the heterodimeric protein (e.g., a heterodimeric antibody or a bispecific antibody) include, but are not limited to, human CD3 (or CD3 (Cluster of Differentiation) complex), CD16, NKG2D, NKp46, CD2, CD28, CD25, CD64, and CD89.

The target cell can be a cell that is native or foreign to humans. In a native target cell, the cell may have been transformed to be a malignant cell or pathologically modified (e.g., a native target cell infected with a virus, a plasmodium, or a bacterium). In a foreign target cell, the cell is an invading pathogen, such as a bacterium, a plasmodium, or a virus.

The target antigen is expressed on a target cell in a diseased condition (e.g., an inflammatory disease, a proliferative disease (e.g., cancer), an immunological disorder, a neurological disease, a neurodegenerative disease, an autoimmune disease, an infectious disease (e.g., a viral infection or a parasitic infection), an allergic reaction, a graft-versus-host disease or a host-versus-graft disease). A target antigen is not effector antigen. Examples of the target antigens include, but are not limited to, BCMA, EpCAM (Epithelial Cell Adhesion Molecule), CCR5 (Chemokine Receptor type 5), CD19, HER (Human Epidermal Growth Factor Receptor)-2/neu, HER-3, HER-4, EGFR (Epidermal Growth Factor Receptor), PSMA, CEA, MUC-1 (Mucin), MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, CIhCG, Lewis-Y, CD20, CD33, CD30, ganglioside GD3, 9-O-Acetyl-GD3, GM2, Globo H, fucosyl GM1, Poly SA, GD2, Carboanhydrase IX (MN/CA IX), CD44v6, Shh (Sonic Hedgehog), Wue-1, Plasma Cell Antigen, (membrane-bound) IgE, MCSP (Melanoma Chondroitin Sulfate Proteoglycan), CCR8, TNF-alpha precursor, STEAP, mesothelin, A33 Antigen, PSCA (Prostate Stem Cell Antigen), Ly-6; desmoglein 4, E-cadherin neoepitope, Fetal Acetylcholine Receptor, CD25, CA19-9 marker, CA-125 marker and MIS (Muellerian Inhibitory Substance) Receptor type II, sTn (sialylated Tn antigen; TAG-72), FAP (fibroblast activation antigen), endosialin, EGFRvIII, LG, SAS and CD63.

In some embodiments, the heterodimeric protein (e.g., bispecific antibody) as described herein comprises a full-length human antibody, wherein a first antibody variable domain of the heterodimeric protein is capable of recruiting the activity of a human immune effector cell by specifically binding to an effector antigen (e.g., CD3 antigen) located on the human immune effector cell, wherein a second antibody variable domain of the heterodimeric protein is capable of specifically binding to a target antigen (e.g., CD20 antigen or EpCAM), wherein the first and second antibody variable domain of the heterodimeric protein comprise amino acid modifications at positions 223, 225, and 228 (e.g., (C223E or C223R), (E225R), and (P228E or P228R)) in the hinge region and at position 409 or 368 (e.g., K409R or L368E (EU numbering scheme)) in the CH3 region of human IgG2 (SEQ ID NO: 493).

In some embodiments, the first and second antibody variable domains of the heterodimeric protein comprise amino acid modifications at positions 221 and 228 (e.g., (D221R or D221E) and (P228R or P228E)) in the hinge region and at position 409 or 368 (e.g., K409R or L368E (EU numbering scheme)) in the CH3 region of human IgG1 (SEQ ID NO: 494).

In some embodiments, the first and second antibody variable domains of the heterodimeric protein comprise amino acid modifications at positions 228 (e.g., (P228E or P228R)) in the hinge region and at position 409 or 368 (e.g., R409 or L368E (EU numbering scheme)) in the CH3 region of human IgG4 (SEQ ID NO: 495).

In another embodiment, the first antibody variable domain of the heterodimeric protein comprises a VH region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398, or 400; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399, and the second antibody variable domain of the heterodimeric protein comprises VH region comprising the VH sequence shown in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 125, 127, 313, 314, 363, or 365; and/or a VL region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315, or 364.

In another embodiment, the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 112; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 38.

In another embodiment, the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 417; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 156; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225. The VH CDR1 of the first antibody variable domain may further comprise the sequence of S, FS, TFS, FTFS or GFTFS immediately preceding the sequence shown in SEQ ID NO: 331. For example, the VH CDR1 of the first antibody variable domain may comprise the sequence shown in SEQ ID NO: 333. The VH CDR2 of the first antibody variable domain may further comprise the sequence of F or FI immediately preceding the sequence shown in SEQ ID NO: 417 and/or the sequence of S, SD, SDH, SDHN, SDHNP, SDHNPS, SDHNPSV, SDHNPSVK, or SDHNPSVKG immediately following the sequence shown in SEQ ID NO: 417. For example, the VH CDR2 of the first antibody variable domain may comprise the sequence shown in SEQ ID NO: 336. The VH CDR1 of the second antibody variable domain may further comprise the sequence of S, FS, TFS, FTFS or GFTFS immediately preceding the sequence shown in SEQ ID NO: 156. For example, the VH CDR1 of the second antibody variable domain may comprise the sequence shown in SEQ ID NO: 157. The VH CDR2 of the second antibody variable domain may further comprise the sequence of A or AI immediately preceding the sequence shown in SEQ ID NO: 159 and/or the sequence of L, LP, LPY, LPYA, LPYAD, LPYADS, LPYADSV, LPYADSVK, or LPYADSVKG immediately following the sequence shown in SEQ ID NO: 159. For example, the VH CDR2 of the second antibody variable domain may comprise the sequence shown in SEQ ID NO: 158.

In another embodiment, the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 332 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 151; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 158; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225. The VH CDR1 of the first antibody variable domain may further comprise the sequence of Y, YM or YMT immediately following the sequence shown in SEQ ID NO: 332. For example, the VH CDR1 of the first antibody variable domain may comprise the sequence shown in SEQ ID NO: 333. The VH CDR1 of the second antibody variable domain may further comprise the sequence P, PM, or PMS immediately following the sequence shown in SEQ ID NO: 151. For example, the VH CDR1 of the second antibody variable domain may comprise the sequence shown in SEQ ID NO: 157.

In another embodiment, the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 401 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 404; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 406; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 439; and the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 156; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225. The VH CDR1 of the first antibody variable domain may further comprise the sequence of S, FS, TFS, FTFS or GFTFS immediately preceding the sequence shown in SEQ ID NO: 401. For example, the VH CDR1 of the first antibody variable domain comprises the sequence shown in SEQ ID NO: 408. The VH CDR2 of the first antibody variable domain may further comprise the sequence of R or RI immediately preceding the sequence shown in SEQ ID NO: 404 and/or the sequence of T, TY, TYY, TYYA, TYYAE, TYYAES, TYYAESV, TYYAESVK, or TYYAESVKG immediately following the sequence shown in SEQ ID NO: 404. For example, the bispecific antibody of claim 49, wherein the VH CDR2 of the first antibody variable domain comprises the sequence shown in SEQ ID NO: 405. The VH CDR1 of the second antibody variable domain may further comprise the sequence of S, FS, TFS, FTFS or GFTFS immediately preceding the sequence shown in SEQ ID NO: 156. For example, the VH CDR1 of the second antibody variable domain comprises the sequence shown in SEQ ID NO: 157. The VH CDR2 of the second antibody variable domain may further comprise the sequence of A or AI immediately preceding the sequence shown in SEQ ID NO: 159 and/or the sequence of L, LP, LPY, LPYA, LPYAD, LPYADS, LPYADSV, LPYADSVK, or LPYADSVKG immediately following the sequence shown in SEQ ID NO: 159. For example, the VH CDR2 of the second antibody variable domain may comprise the sequence shown in SEQ ID NO: 158.

In another embodiment, the first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 407 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 405; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 406; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 439; and the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 151; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 158; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225. The VH CDR1 of the first antibody variable domain may further comprise the sequence of A, AM or AMN immediately following the sequence shown in SEQ ID NO: 407. For example, the VH CDR1 of the first antibody variable domain may comprise the sequence shown in SEQ ID NO: 408. The VH CDR1 of the second antibody variable domain may further comprise the sequence P, PM, or PMS immediately following the sequence shown in SEQ ID NO: 151. For example, the VH CDR1 of the second antibody variable domain may comprise the sequence shown in SEQ ID NO: 157.

The antibodies useful in the present invention can encompass monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (e.g., a domain antibody), humanized antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies may be murine, rat, human, or any other origin (including chimeric or humanized antibodies).

In some embodiments, the BCMA or CD3 antibody as described herein is a monoclonal antibody. For example, the BCMA or CD3 antibody is a humanized monoclonal antibody or a chimeric monoclonal antibody.

In some embodiments, the antibody comprises a modified constant region, such as, for example without limitation, a constant region that has increased potential for provoking an immune response. For example, the constant region may be modified to have increased affinity to an Fc gamma receptor such as, e.g., Fc.gamma.RI, Fc.gamma.RIIA, or Fc.gamma.III.

In some embodiments, the antibody comprises a modified constant region, such as a constant region that is immunologically inert, that is, having a reduced potential for provoking an immune response. In some embodiments, the constant region is modified as described in Eur. J. Immunol., 29:2613-2624, 1999; PCT Application No. PCT/GB99/01441; and/or UK Patent Application No. 98099518. The Fc can be human IgG1, human IgG2, human IgG3, or human IgG4. The Fc can be human IgG2 containing the mutation A330P331 to S330S331 (IgG2.DELTA.a), in which the amino acid residues are numbered with reference to the wild type IgG2 sequence. Eur. J. Immunol., 29:2613-2624, 1999. In some embodiments, the antibody comprises a constant region of IgG.sub.4 comprising the following mutations (Armour et al., Molecular Immunology 40 585-593, 2003): E233F234L235 to P233V234A235 (IgG4.DELTA.c), in which the numbering is with reference to wild type IgG4. In yet another embodiment, the Fc is human IgG4 E233F234L235 to P233V234A235 with deletion G236 (IgG4.DELTA.b). In another embodiment, the Fc is any human IgG4 Fc (IgG4, IgG4.DELTA.b or IgG4.DELTA.c) containing hinge stabilizing mutation S228 to P228 (Aalberse et al., Immunology 105, 9-19, 2002). In another embodiment, the Fc can be aglycosylated Fc.

In some embodiments, the constant region is aglycosylated by mutating the oligosaccharide attachment residue (such as Asn297) and/or flanking residues that are part of the glycosylation recognition sequence in the constant region. In some embodiments, the constant region is aglycosylated for N-linked glycosylation enzymatically. The constant region may be aglycosylated for N-linked glycosylation enzymatically or by expression in a glycosylation deficient host cell.

In some embodiments, the constant region has a modified constant region that removes or reduces Fc gamma receptor binding. For example, the Fc can be human IgG2 containing the mutation D265, in which the amino acid residues are numbered with reference to the wild type IgG2 sequence (SEQ ID NO: 493). Accordingly, in some embodiments, the constant region has a modified constant region having the sequence shown in SEQ ID NO: 496:

TABLE-US-00009 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCRVRCPRCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKC KVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSRLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK.

In some embodiments, the constant region has a modified constant region having the sequence shown in SEQ ID NO: 497:

TABLE-US-00010 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCEVECPECPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKC KVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCEVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK.

One way of determining binding affinity of antibodies to BCMA or CD3 is by measuring binding affinity of monofunctional Fab fragments of the antibody. To obtain monofunctional Fab fragments, an antibody (for example, IgG) can be cleaved with papain or expressed recombinantly. The affinity of a BCMA Fab fragment of an antibody can be determined by surface plasmon resonance (Biacore.TM.3000.TM. surface plasmon resonance (SPR) system, Biacore.TM., INC, Piscataway N.J.) equipped with pre-immobilized streptavidin sensor chips (SA) or anti-mouse Fc or anti-human Fc using HBS-EP running buffer (0.01M HEPES, pH 7.4, 0.15 NaCl, 3 mM EDTA, 0.005% v/v Surfactant P20). Biotinylated or Fc fusion human BCMA can be diluted into HBS-EP buffer to a concentration of less than 0.5 .mu.g/mL and injected across the individual chip channels using variable contact times, to achieve two ranges of antigen density, either 50-200 response units (RU) for detailed kinetic studies or 800-1,000 RU for screening assays. Regeneration studies have shown that 25 mM NaOH in 25% v/v ethanol effectively removes the bound Fab while keeping the activity of BCMA on the chip for over 200 injections. Typically, serial dilutions (spanning concentrations of 0.1-10.times. estimated K.sub.D) of purified Fab samples are injected for 1 min at 100 .mu.L/minute and dissociation times of up to 2 hours are allowed. The concentrations of the Fab proteins are determined by ELISA and/or SDS-PAGE electrophoresis using a Fab of known concentration (as determined by amino acid analysis) as a standard. Kinetic association rates (k.sub.on) and dissociation rates (k.sub.off) are obtained simultaneously by fitting the data globally to a 1:1 Langmuir binding model (Karlsson, R. Roos, H. Fagerstam, L. Petersson, B. (1994). Methods Enzymology 6. 99-110) using the BIAevaluation program. Equilibrium dissociation constant (K.sub.D) values are calculated as k.sub.off/k.sub.on. This protocol is suitable for use in determining binding affinity of an antibody to any BCMA, including human BCMA, BCMA of another mammal (such as mouse BCMA, rat BCMA, or primate BCMA), as well as different forms of BCMA (e.g., glycosylated BCMA). Binding affinity of an antibody is generally measured at 25.degree. C., but can also be measured at 37.degree. C.

The antibodies as described herein may be made by any method known in the art. For the production of hybridoma cell lines, the route and schedule of immunization of the host animal are generally in keeping with established and conventional techniques for antibody stimulation and production, as further described herein. General techniques for production of human and mouse antibodies are known in the art and/or are described herein.

It is contemplated that any mammalian subject including humans or antibody producing cells therefrom can be manipulated to serve as the basis for production of mammalian, including human and hybridoma cell lines. Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantar, and/or intradermally with an amount of immunogen, including as described herein.

Hybridomas can be prepared from the lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique of Kohler, B. and Milstein, C., Nature 256:495-497, 1975 or as modified by Buck, D. W., et al., In Vitro, 18:377-381, 1982. Available myeloma lines, including but not limited to X63-Ag8.653 and those from the Salk Institute, Cell Distribution Center, San Diego, Calif., USA, may be used in the hybridization. Generally, the technique involves fusing myeloma cells and lymphoid cells using a fusogen such as polyethylene glycol, or by electrical means well known to those skilled in the art. After the fusion, the cells are separated from the fusion medium and grown in a selective growth medium, such as hypoxanthine-aminopterin-thymidine (HAT) medium, to eliminate unhybridized parent cells. Any of the media described herein, supplemented with or without serum, can be used for culturing hybridomas that secrete monoclonal antibodies. As another alternative to the cell fusion technique, EBV immortalized B cells may be used to produce the monoclonal antibodies of the subject invention. The hybridomas are expanded and subcloned, if desired, and supernatants are assayed for anti-immunogen activity by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).

Hybridomas that may be used as source of antibodies encompass all derivatives, progeny cells of the parent hybridomas that produce monoclonal antibodies specific for BCMA, CD3, or portions thereof.

Hybridomas that produce such antibodies may be grown in vitro or in vivo using known procedures. The monoclonal antibodies may be isolated from the culture media or body fluids, by conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration, if desired. Undesired activity, if present, can be removed, for example, by running the preparation over adsorbents made of the immunogen attached to a solid phase and eluting or releasing the desired antibodies off the immunogen. Immunization of a host animal with a human BCMA or CD3, or a fragment containing the target amino acid sequence conjugated to a protein that is immunogenic in the species to be immunized, e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor using a bifunctional or derivatizing agent, for example, maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCl.sub.2, or R.sup.1N.dbd.C.dbd.NR, where R and R.sup.1 are different alkyl groups, can yield a population of antibodies (e.g., monoclonal antibodies).

If desired, the antibody (monoclonal or polyclonal) of interest may be sequenced and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g. Tiller et al., J. Immunol. Methods 329, 112, 2008; U.S. Pat. No. 7,314,622.

In an alternative, the polynucleotide sequence may be used for genetic manipulation to "humanize" the antibody or to improve the affinity, or other characteristics of the antibody. For example, the constant region may be engineered to more nearly resemble human constant regions to avoid immune response if the antibody is used in clinical trials and treatments in humans. It may be desirable to genetically manipulate the antibody sequence to obtain greater affinity to BCMA or CD3 and greater efficacy in inhibiting BCMA.

There are four general steps to humanize a monoclonal antibody. These are: (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains (2) designing the humanized antibody, i.e., deciding which antibody framework region to use during the humanizing process (3) the actual humanizing methodologies/techniques and (4) the transfection and expression of the humanized antibody. See, for example, U.S. Pat. Nos. 4,816,567; 5,807,715; 5,866,692; 6,331,415; 5,530,101; 5,693,761; 5,693,762; 5,585,089; and 6,180,370.

A number of "humanized" antibody molecules comprising an antigen binding site derived from a non-human immunoglobulin have been described, including chimeric antibodies having rodent or modified rodent V regions and their associated CDRs fused to human constant regions. See, for example, Winter et al. Nature 349:293-299, 1991, Lobuglio et al. Proc. Nat. Acad. Sci. USA 86:4220-4224, 1989, Shaw et al. J Immunol. 138:4534-4538, 1987, and Brown et al. Cancer Res. 47:3577-3583, 1987. Other references describe rodent CDRs grafted into a human supporting framework region (FR) prior to fusion with an appropriate human antibody constant region. See, for example, Riechmann et al. Nature 332:323-327, 1988, Verhoeyen et al. Science 239:1534-1536, 1988, and Jones et al. Nature 321:522-525, 1986. Another reference describes rodent CDRs supported by recombinantly engineered rodent framework regions. See, for example, European Patent Publication No. 0519596. These "humanized" molecules are designed to minimize unwanted immunological response toward rodent anti-human antibody molecules which limits the duration and effectiveness of therapeutic applications of those moieties in human recipients. For example, the antibody constant region can be engineered such that it is immunologically inert (e.g., does not trigger complement lysis). See, e.g. PCT Publication No. PCT/GB99/01441; UK Patent Application No. 9809951.8. Other methods of humanizing antibodies that may also be utilized are disclosed by Daugherty et al., Nucl. Acids Res. 19:2471-2476, 1991, and in U.S. Pat. Nos. 6,180,377; 6,054,297; 5,997,867; 5,866,692; 6,210,671; and 6,350,861; and in PCT Publication No. WO 01/27160.

The general principles related to humanized antibodies discussed above are also applicable to customizing antibodies for use, for example, in dogs, cats, primate, equines and bovines. Further, one or more aspects of humanizing an antibody described herein may be combined, e.g., CDR grafting, framework mutation and CDR mutation.

In one variation, fully human antibodies may be obtained by using commercially available mice that have been engineered to express specific human immunoglobulin proteins. Transgenic animals that are designed to produce a more desirable (e.g., fully human antibodies) or more robust immune response may also be used for generation of humanized or human antibodies. Examples of such technology are Xenomouse.TM. from Abgenix, Inc. (Fremont, Calif.) and HuMAb-Mouse.RTM. and TC Mouse.TM. from Medarex, Inc. (Princeton, N.J.).

In an alternative, antibodies may be made recombinantly and expressed using any method known in the art. In another alternative, antibodies may be made recombinantly by phage display technology. See, for example, U.S. Pat. Nos. 5,565,332; 5,580,717; 5,733,743; and 6,265,150; and Winter et al., Annu. Rev. Immunol. 12:433-455, 1994. Alternatively, the phage display technology (McCafferty et al., Nature 348:552-553, 1990) can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunized donors. According to this technique, antibody V domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. Thus, the phage mimics some of the properties of the B cell. Phage display can be performed in a variety of formats; for review see, e.g., Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3:564-571, 1993. Several sources of V-gene segments can be used for phage display. Clackson et al., Nature 352:624-628, 1991, isolated a diverse array of anti-oxazolone antibodies from a small random combinatorial library of V genes derived from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Mark et al., J. Mol. Biol. 222:581-597, 1991, or Griffith et al., EMBO J. 12:725-734, 1993. In a natural immune response, antibody genes accumulate mutations at a high rate (somatic hypermutation). Some of the changes introduced will confer higher affinity, and B cells displaying high-affinity surface immunoglobulin are preferentially replicated and differentiated during subsequent antigen challenge. This natural process can be mimicked by employing the technique known as "chain shuffling." (Marks et al., Bio/Technol. 10:779-783, 1992). In this method, the affinity of "primary" human antibodies obtained by phage display can be improved by sequentially replacing the heavy and light chain V region genes with repertoires of naturally occurring variants (repertoires) of V domain genes obtained from unimmunized donors. This technique allows the production of antibodies and antibody fragments with affinities in the pM-nM range. A strategy for making very large phage antibody repertoires (also known as "the mother-of-all libraries") has been described by Waterhouse et al., Nucl. Acids Res. 21:2265-2266, 1993. Gene shuffling can also be used to derive human antibodies from rodent antibodies, where the human antibody has similar affinities and specificities to the starting rodent antibody. According to this method, which is also referred to as "epitope imprinting", the heavy or light chain V domain gene of rodent antibodies obtained by phage display technique is replaced with a repertoire of human V domain genes, creating rodent-human chimeras. Selection on antigen results in isolation of human variable regions capable of restoring a functional antigen binding site, i.e., the epitope governs (imprints) the choice of partner. When the process is repeated in order to replace the remaining rodent V domain, a human antibody is obtained (see PCT Publication No. WO 93/06213). Unlike traditional humanization of rodent antibodies by CDR grafting, this technique provides completely human antibodies, which have no framework or CDR residues of rodent origin.

Antibodies may be made recombinantly by first isolating the antibodies and antibody producing cells from host animals, obtaining the gene sequence, and using the gene sequence to express the antibody recombinantly in host cells (e.g., CHO cells). Another method which may be employed is to express the antibody sequence in plants (e.g., tobacco) or transgenic milk. Methods for expressing antibodies recombinantly in plants or milk have been disclosed. See, for example, Peeters, et al. Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Pollock, et al., J Immunol Methods 231:147, 1999. Methods for making derivatives of antibodies, e.g., humanized, single chain, etc. are known in the art.

Immunoassays and flow cytometry sorting techniques such as fluorescence activated cell sorting (FACS) can also be employed to isolate antibodies that are specific for BCMA, CD3, or tumor antigens of interest.

The antibodies as described herein can be bound to many different carriers. Carriers can be active and/or inert. Examples of well-known carriers include polypropylene, polystyrene, polyethylene, dextran, nylon, amylases, glass, natural and modified celluloses, polyacrylamides, agaroses, and magnetite. The nature of the carrier can be either soluble or insoluble for purposes of the invention. Those skilled in the art will know of other suitable carriers for binding antibodies, or will be able to ascertain such, using routine experimentation. In some embodiments, the carrier comprises a moiety that targets the myocardium.

DNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). The hybridoma cells serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors (such as expression vectors disclosed in PCT Publication No. WO 87/04462), which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. See, e.g., PCT Publication No. WO 87/04462. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant regions in place of the homologous murine sequences, Morrison et al., Proc. Nat. Acad. Sci. 81:6851, 1984, or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. In that manner, "chimeric" or "hybrid" antibodies are prepared that have the binding specificity of a monoclonal antibody herein.

The BCMA or tumor antigen of interest antibodies as described herein can be identified or characterized using methods known in the art, whereby reduction of BCMA or other tumor antigen expression levels are detected and/or measured. In some embodiments, a BCMA antibody is identified by incubating a candidate agent with BCMA and monitoring binding and/or attendant reduction of BCMA expression levels. The binding assay may be performed with purified BCMA polypeptide(s), or with cells naturally expressing, or transfected to express, BCMA polypeptide(s). In one embodiment, the binding assay is a competitive binding assay, where the ability of a candidate antibody to compete with a known BCMA antibody for BCMA binding is evaluated. The assay may be performed in various formats, including the ELISA format.

Following initial identification, the activity of a candidate BCMA, CD3, or other tumor antigen antibody can be further confirmed and refined by bioassays, known to test the targeted biological activities. Alternatively, bioassays can be used to screen candidates directly. Some of the methods for identifying and characterizing antibodies are described in detail in the Examples.

BCMA, CD3, or other tumor antigen antibodies may be characterized using methods well known in the art. For example, one method is to identify the epitope to which it binds, or "epitope mapping." There are many methods known in the art for mapping and characterizing the location of epitopes on proteins, including solving the crystal structure of an antibody-antigen complex, competition assays, gene fragment expression assays, and synthetic peptide-based assays, as described, for example, in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. In an additional example, epitope mapping can be used to determine the sequence to which an antibody binds. Epitope mapping is commercially available from various sources, for example, Pepscan Systems (Edelhertweg 15, 8219 PH Lelystad, The Netherlands). The epitope can be a linear epitope, i.e., contained in a single stretch of amino acids, or a conformational epitope formed by a three-dimensional interaction of amino acids that may not necessarily be contained in a single stretch. Peptides of varying lengths (e.g., at least 4-6 amino acids long) can be isolated or synthesized (e.g., recombinantly) and used for binding assays with a BCMA, CD3, or other tumor antigen antibody. In another example, the epitope to which the BCMA, CD3, or other tumor antigen antibody binds can be determined in a systematic screening by using overlapping peptides derived from the BCMA, CD3, or other tumor antigen sequence and determining binding by the BCMA, CD3, or other tumor antigen antibody. According to the gene fragment expression assays, the open reading frame encoding BCMA, CD3, or other tumor antigen is fragmented either randomly or by specific genetic constructions and the reactivity of the expressed fragments of BCMA, CD3, or other tumor antigen with the antibody to be tested is determined. The gene fragments may, for example, be produced by PCR and then transcribed and translated into protein in vitro, in the presence of radioactive amino acids. The binding of the antibody to the radioactively labeled BCMA, CD3, or other tumor antigen fragments is then determined by immunoprecipitation and gel electrophoresis. Certain epitopes can also be identified by using large libraries of random peptide sequences displayed on the surface of phage particles (phage libraries). Alternatively, a defined library of overlapping peptide fragments can be tested for binding to the test antibody in simple binding assays. In an additional example, mutagenesis of an antigen binding domain, domain swapping experiments and alanine scanning mutagenesis can be performed to identify residues required, sufficient, and/or necessary for epitope binding. For example, domain swapping experiments can be performed using a mutant BCMA, CD3, or other tumor antigen in which various fragments of the BCMA, CD3, or other tumor antigen protein have been replaced (swapped) with sequences from BCMA from another species (e.g., mouse), or a closely related, but antigenically distinct protein (e.g., Trop-1). By assessing binding of the antibody to the mutant BCMA, CD3, or other tumor antigen, the importance of the particular BCMA, CD3, or other tumor antigen fragment to antibody binding can be assessed.

Yet another method which can be used to characterize a BCMA, CD3, or other tumor antigen antibody is to use competition assays with other antibodies known to bind to the same antigen, i.e., various fragments on BCMA, CD3, or other tumor antigen, to determine if the BCMA, CD3, or other tumor antigen antibody binds to the same epitope as other antibodies. Competition assays are well known to those of skill in the art.

An expression vector can be used to direct expression of a BCMA, CD3, or other tumor antigen antibody. One skilled in the art is familiar with administration of expression vectors to obtain expression of an exogenous protein in vivo. See, e.g., U.S. Pat. Nos. 6,436,908; 6,413,942; and 6,376,471. Administration of expression vectors includes local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. In another embodiment, the expression vector is administered directly to the sympathetic trunk or ganglion, or into a coronary artery, atrium, ventrical, or pericardium.

Targeted delivery of therapeutic compositions containing an expression vector, or subgenomic polynucleotides can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol., 1993, 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer, J. A. Wolff, ed., 1994; Wu et al., J. Biol. Chem., 263:621, 1988; Wu et al., J. Biol. Chem., 269:542, 1994; Zenke et al., Proc. Natl. Acad. Sci. USA, 87:3655, 1990; and Wu et al., J. Biol. Chem., 266:338, 1991. Therapeutic compositions containing a polynucleotide are administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 .mu.g to about 2 mg, about 5 .mu.g to about 500 .mu.g, and about 20 .mu.g to about 100 .mu.g of DNA can also be used during a gene therapy protocol. The therapeutic polynucleotides and polypeptides can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (see generally, Jolly, Cancer Gene Therapy, 1:51, 1994; Kimura, Human Gene Therapy, 5:845, 1994; Connelly, Human Gene Therapy, 1995, 1:185; and Kaplitt, Nature Genetics, 6:148, 1994). Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters. Expression of the coding sequence can be either constitutive or regulated.

Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., PCT Publication Nos. WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; WO 93/11230; WO 93/10218; WO 91/02805; U.S. Pat. Nos. 5,219,740 and 4,777,127; GB Pat. No. 2,200,651; and EP Pat. No. 0 345 242), alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)), and adeno-associated virus (AAV) vectors (see, e.g., PCT Publication Nos. WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984 and WO 95/00655). Administration of DNA linked to killed adenovirus as described in Curiel, Hum. Gene Ther., 1992, 3:147 can also be employed.

Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther., 3:147, 1992); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem., 264:16985, 1989); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; PCT Publication Nos. WO 95/07994; WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in PCT Publication No. WO 90/11092 and U.S. Pat. No. 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; PCT Publication Nos. WO 95/13796; WO 94/23697; WO 91/14445; and EP 0524968. Additional approaches are described in Philip, Mol. Cell Biol., 14:2411, 1994 and in Woffendin, Proc. Natl. Acad. Sci., 91:1581, 1994.

In some embodiments, the invention encompasses compositions, including pharmaceutical compositions, comprising antibodies described herein or made by the methods and having the characteristics described herein. As used herein, compositions comprise one or more antibodies that bind to CD3 and a tumor antigen (e.g BCMA), and/or one or more polynucleotides comprising sequences encoding one or more these antibodies. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients including buffers, which are well known in the art.

The invention also provides methods of making any of these antibodies. The antibodies of this invention can be made by procedures known in the art. The polypeptides can be produced by proteolytic or other degradation of the antibodies, by recombinant methods (i.e., single or fusion polypeptides) as described above or by chemical synthesis. Polypeptides of the antibodies, especially shorter polypeptides up to about 50 amino acids, are conveniently made by chemical synthesis. Methods of chemical synthesis are known in the art and are commercially available. For example, an antibody could be produced by an automated polypeptide synthesizer employing the solid phase method. See also, U.S. Pat. Nos. 5,807,715; 4,816,567; and 6,331,415.

Heteroconjugate antibodies, comprising two covalently joined antibodies, are also within the scope of the invention. Such antibodies have been used to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (PCT Publication Nos. WO 91/00360 and WO 92/200373; EP 03089). Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents and techniques are well known in the art, and are described in U.S. Pat. No. 4,676,980.

Chimeric or hybrid antibodies also may be prepared in vitro using known methods of synthetic protein chemistry, including those involving cross-linking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate.

In the recombinant humanized antibodies, the Fc.gamma. portion can be modified to avoid interaction with Fc.gamma. receptor and the complement and immune systems. The techniques for preparation of such antibodies are described in WO 99/58572. For example, the constant region may be engineered to more resemble human constant regions to avoid immune response if the antibody is used in clinical trials and treatments in humans. See, for example, U.S. Pat. Nos. 5,997,867 and 5,866,692.

The invention encompasses modifications to the antibodies and polypeptides of the invention variants as described herein, including functionally equivalent antibodies which do not significantly affect their properties and variants which have enhanced or decreased activity and/or affinity. For example, the amino acid sequence may be mutated to obtain an antibody with the desired binding affinity to BCMA and/or CD3. Modification of polypeptides is routine practice in the art and need not be described in detail herein. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids which do not significantly deleteriously change the functional activity, or which mature (enhance) the affinity of the polypeptide for its ligand, or use of chemical analogs.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue or the antibody fused to an epitope tag. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody of an enzyme or a polypeptide which increases the half-life of the antibody in the blood circulation.

Substitution variants have at least one amino acid residue in the antibody molecule removed and a different residue inserted in its place. The sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but FR alterations are also contemplated. Conservative substitutions are shown in Table 5 under the heading of "conservative substitutions." If such substitutions result in a change in biological activity, then more substantial changes, denominated "exemplary substitutions" in Table 5, or as further described below in reference to amino acid classes, may be introduced and the products screened.

TABLE-US-00011 TABLE 5 Amino Acid Substitutions Original Residue (naturally occurring amino Conservative acid) Substitutions Exemplary Substitutions Ala (A) Val Val; Leu; Ile Arg (R) Lys Lys; Gln; Asn Asn (N) Gln Gln; His; Asp, Lys; Arg Asp (D) Glu Glu; Asn Cys (C) Ser Ser; Ala Gln (Q) Asn Asn; Glu Glu (E) Asp Asp; Gln Gly (G) Ala Ala His (H) Arg Asn; Gln; Lys; Arg Ile (I) Leu Leu; Val; Met; Ala; Phe; Norleucine Leu (L) Ile Norleucine; Ile; Val; Met; Ala; Phe Lys (K) Arg Arg; Gln; Asn Met (M) Leu Leu; Phe; Ile Phe (F) Tyr Leu; Val; Ile; Ala; Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr Tyr; Phe Tyr (Y) Phe Trp; Phe; Thr; Ser Val (V) Leu Ile; Leu; Met; Phe; Ala; Norleucine

Substantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring amino acid residues are divided into groups based on common side-chain properties: (1) Non-polar: Norleucine, Met, Ala, Val, Leu, lie; (2) Polar without charge: Cys, Ser, Thr, Asn, Gin; (3) Acidic (negatively charged): Asp, Glu; (4) Basic (positively charged): Lys, Arg; (5) Residues that influence chain orientation: Gly, Pro; and (6) Aromatic: Trp, Tyr, Phe, His.

Non-conservative substitutions are made by exchanging a member of one of these classes for another class.

Any cysteine residue not involved in maintaining the proper conformation of the antibody also may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant cross-linking. Conversely, cysteine bond(s) may be added to the antibody to improve its stability, particularly where the antibody is an antibody fragment such as an Fv fragment.

Amino acid modifications can range from changing or modifying one or more amino acids to complete redesign of a region, such as the variable region. Changes in the variable region can alter binding affinity and/or specificity. In some embodiments, no more than one to five conservative amino acid substitutions are made within a CDR domain. In other embodiments, no more than one to three conservative amino acid substitutions are made within a CDR domain. In still other embodiments, the CDR domain is CDR H3 and/or CDR L3.

Modifications also include glycosylated and nonglycosylated polypeptides, as well as polypeptides with other post-translational modifications, such as, for example, glycosylation with different sugars, acetylation, and phosphorylation. Antibodies are glycosylated at conserved positions in their constant regions (Jefferis and Lund, Chem. Immunol. 65:111-128, 1997; Wright and Morrison, TibTECH 15:26-32, 1997). The oligosaccharide side chains of the immunoglobulins affect the protein's function (Boyd et al., Mol. Immunol. 32:1311-1318, 1996; Wittwe and Howard, Biochem. 29:4175-4180, 1990) and the intramolecular interaction between portions of the glycoprotein, which can affect the conformation and presented three-dimensional surface of the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, Current Opin. Biotech. 7:409-416, 1996). Oligosaccharides may also serve to target a given glycoprotein to certain molecules based upon specific recognition structures. Glycosylation of antibodies has also been reported to affect antibody-dependent cellular cytotoxicity (ADCC). In particular, CHO cells with tetracycline-regulated expression of .beta.(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase catalyzing formation of bisecting GlcNAc, was reported to have improved ADCC activity (Umana et al., Mature Biotech. 17:176-180, 1999).

Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).

The glycosylation pattern of antibodies may also be altered without altering the underlying nucleotide sequence. Glycosylation largely depends on the host cell used to express the antibody. Since the cell type used for expression of recombinant glycoproteins, e.g. antibodies, as potential therapeutics is rarely the native cell, variations in the glycosylation pattern of the antibodies can be expected (see, e.g. Hse et al., J. Biol. Chem. 272:9062-9070, 1997).

In addition to the choice of host cells, factors that affect glycosylation during recombinant production of antibodies include growth mode, media formulation, culture density, oxygenation, pH, purification schemes and the like. Various methods have been proposed to alter the glycosylation pattern achieved in a particular host organism including introducing or overexpressing certain enzymes involved in oligosaccharide production (U.S. Pat. Nos. 5,047,335; 5,510,261 and 5,278,299). Glycosylation, or certain types of glycosylation, can be enzymatically removed from the glycoprotein, for example, using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3. In addition, the recombinant host cell can be genetically engineered to be defective in processing certain types of polysaccharides. These and similar techniques are well known in the art.

Other methods of modification include using coupling techniques known in the art, including, but not limited to, enzymatic means, oxidative substitution and chelation. Modifications can be used, for example, for attachment of labels for immunoassay. Modified polypeptides are made using established procedures in the art and can be screened using standard assays known in the art, some of which are described below and in the Examples.

In some embodiments of the invention, the antibody comprises a modified constant region, such as a constant region that has increased affinity to a human Fc gamma receptor, is immunologically inert or partially inert, e.g., does not trigger complement mediated lysis, does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC), or does not activate macrophages; or has reduced activities (compared to the unmodified antibody) in any one or more of the following: triggering complement mediated lysis, stimulating antibody-dependent cell mediated cytotoxicity (ADCC), or activating microglia. Different modifications of the constant region may be used to achieve optimal level and/or combination of effector functions. See, for example, Morgan et al., Immunology 86:319-324, 1995; Lund et al., J. Immunology 157:4963-9 157:4963-4969, 1996; Idusogie et al., J. Immunology 164:4178-4184, 2000; Tao et al., J. Immunology 143: 2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, the constant region is modified as described in Eur. J. Immunol., 1999, 29:2613-2624; PCT Application No. PCT/GB99/01441; and/or UK Patent Application No. 9809951.8. In other embodiments, the antibody comprises a human heavy chain IgG2 constant region comprising the following mutations: A330P331 to S330S331 (amino acid numbering with reference to the wild type IgG2 sequence). Eur. J. Immunol., 1999, 29:2613-2624. In still other embodiments, the constant region is aglycosylated for N-linked glycosylation. In some embodiments, the constant region is aglycosylated for N-linked glycosylation by mutating the glycosylated amino acid residue or flanking residues that are part of the N-glycosylation recognition sequence in the constant region. For example, N-glycosylation site N297 may be mutated to A, Q, K, or H. See, Tao et al., J. Immunology 143: 2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, the constant region is aglycosylated for N-linked glycosylation. The constant region may be aglycosylated for N-linked glycosylation enzymatically (such as removing carbohydrate by enzyme PNGase), or by expression in a glycosylation deficient host cell.

Other antibody modifications include antibodies that have been modified as described in PCT Publication No. WO 99/58572. These antibodies comprise, in addition to a binding domain directed at the target molecule, an effector domain having an amino acid sequence substantially homologous to all or part of a constant region of a human immunoglobulin heavy chain. These antibodies are capable of binding the target molecule without triggering significant complement dependent lysis, or cell-mediated destruction of the target. In some embodiments, the effector domain is capable of specifically binding FcRn and/or Fc.gamma.RIIb. These are typically based on chimeric domains derived from two or more human immunoglobulin heavy chain C.sub.H2 domains. Antibodies modified in this manner are particularly suitable for use in chronic antibody therapy, to avoid inflammatory and other adverse reactions to conventional antibody therapy.

The invention includes affinity matured embodiments. For example, affinity matured antibodies can be produced by procedures known in the art (Marks et al., Bio/Technology, 10:779-783, 1992; Barbas et al., Proc Nat. Acad. Sci, USA 91:3809-3813, 1994; Schier et al., Gene, 169:147-155, 1995; Yelton et al., J. Immunol., 155:1994-2004, 1995; Jackson et al., J. Immunol., 154(7):3310-9, 1995, Hawkins et al., J. Mol. Biol., 226:889-896, 1992; and PCT Publication No. WO2004/058184).

The following methods may be used for adjusting the affinity of an antibody and for characterizing a CDR. One way of characterizing a CDR of an antibody and/or altering (such as improving) the binding affinity of a polypeptide, such as an antibody, termed "library scanning mutagenesis". Generally, library scanning mutagenesis works as follows. One or more amino acid positions in the CDR are replaced with two or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acids using art recognized methods. This generates small libraries of clones (in some embodiments, one for every amino acid position that is analyzed), each with a complexity of two or more members (if two or more amino acids are substituted at every position). Generally, the library also includes a clone comprising the native (unsubstituted) amino acid. A small number of clones, e.g., about 20-80 clones (depending on the complexity of the library), from each library are screened for binding affinity to the target polypeptide (or other binding target), and candidates with increased, the same, decreased, or no binding are identified. Methods for determining binding affinity are well-known in the art. Binding affinity may be determined using Biacore.TM. surface plasmon resonance analysis, which detects differences in binding affinity of about 2-fold or greater. Biacore.TM. is particularly useful when the starting antibody already binds with a relatively high affinity, for example a K.sub.D of about 10 nM or lower. Screening using Biacore.TM. surface plasmon resonance is described in the Examples, herein.

Binding affinity may be determined using Kinexa Biocensor, scintillation proximity assays, ELISA, ORIGEN immunoassay (IGEN), fluorescence quenching, fluorescence transfer, and/or yeast display. Binding affinity may also be screened using a suitable bioassay.

In some embodiments, every amino acid position in a CDR is replaced (in some embodiments, one at a time) with all 20 natural amino acids using art recognized mutagenesis methods (some of which are described herein). This generates small libraries of clones (in some embodiments, one for every amino acid position that is analyzed), each with a complexity of 20 members (if all 20 amino acids are substituted at every position).

In some embodiments, the library to be screened comprises substitutions in two or more positions, which may be in the same CDR or in two or more CDRs. Thus, the library may comprise substitutions in two or more positions in one CDR. The library may comprise substitution in two or more positions in two or more CDRs. The library may comprise substitution in 3, 4, 5, or more positions, said positions found in two, three, four, five or six CDRs. The substitution may be prepared using low redundancy codons. See, e.g., Table 2 of Balint et al., Gene 137(1):109-18, 1993.

The CDR may be CDRH3 and/or CDRL3. The CDR may be one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and/or CDRH3. The CDR may be a Kabat CDR, a Chothia CDR, or an extended CDR.

Candidates with improved binding may be sequenced, thereby identifying a CDR substitution mutant which results in improved affinity (also termed an "improved" substitution). Candidates that bind may also be sequenced, thereby identifying a CDR substitution which retains binding.

Multiple rounds of screening may be conducted. For example, candidates (each comprising an amino acid substitution at one or more position of one or more CDR) with improved binding are also useful for the design of a second library containing at least the original and substituted amino acid at each improved CDR position (i.e., amino acid position in the CDR at which a substitution mutant showed improved binding). Preparation, and screening or selection of this library is discussed further below.

Library scanning mutagenesis also provides a means for characterizing a CDR, in so far as the frequency of clones with improved binding, the same binding, decreased binding or no binding also provide information relating to the importance of each amino acid position for the stability of the antibody-antigen complex. For example, if a position of the CDR retains binding when changed to all 20 amino acids, that position is identified as a position that is unlikely to be required for antigen binding. Conversely, if a position of CDR retains binding in only a small percentage of substitutions, that position is identified as a position that is important to CDR function. Thus, the library scanning mutagenesis methods generate information regarding positions in the CDRs that can be changed to many different amino acids (including all 20 amino acids), and positions in the CDRs which cannot be changed or which can only be changed to a few amino acids.

Candidates with improved affinity may be combined in a second library, which includes the improved amino acid, the original amino acid at that position, and may further include additional substitutions at that position, depending on the complexity of the library that is desired, or permitted using the desired screening or selection method. In addition, if desired, adjacent amino acid position can be randomized to at least two or more amino acids. Randomization of adjacent amino acids may permit additional conformational flexibility in the mutant CDR, which may in turn, permit or facilitate the introduction of a larger number of improving mutations. The library may also comprise substitution at positions that did not show improved affinity in the first round of screening.

The second library is screened or selected for library members with improved and/or altered binding affinity using any method known in the art, including screening using Biacore.TM. surface plasmon resonance analysis, and selection using any method known in the art for selection, including phage display, yeast display, and ribosome display.

This invention also provides compositions comprising antibodies conjugated (for example, linked) to an agent that facilitate coupling to a solid support (such as biotin or avidin). For simplicity, reference will be made generally to antibodies with the understanding that these methods apply to any of the BCMA antibody embodiments described herein. Conjugation generally refers to linking these components as described herein. The linking (which is generally fixing these components in proximate association at least for administration) can be achieved in any number of ways. For example, a direct reaction between an agent and an antibody is possible when each possesses a substituent capable of reacting with the other. For example, a nucleophilic group, such as an amino or sulfhydryl group, on one may be capable of reacting with a carbonyl-containing group, such as an anhydride or an acid halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other.

In another aspect, the invention provides a method of making any of the polynucleotides described herein.

Polynucleotides complementarity to any such sequences are also encompassed by the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.

Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a portion thereof) or may comprise a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably, at least about 80% identity, yet more preferably, at least about 90% identity, and most preferably, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a portion thereof.

Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Wis.), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M. O., 1978, A model of evolutionary change in proteins--Matrices for detecting distant relationships. In Dayhoff, M. O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.; Higgins, D. G. and Sharp, P. M., 1989, CABIOS 5:151-153; Myers, E. W. and Muller W., 1988, CABIOS 4:11-17; Robinson, E. D., 1971, Comb. Theor. 11:105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.; Wilbur, W. J. and Lipman, D. J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.

Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementarity sequence).

Suitable "moderately stringent conditions" include prewashing in a solution of 5.times.SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50.degree. C.-65.degree. C., 5.times.SSC, overnight; followed by washing twice at 65.degree. C. for 20 minutes with each of 2.times., 0.5.times. and 0.2.times.SSC containing 0.1% SDS.

As used herein, "highly stringent conditions" or "high stringency conditions" are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50.degree. C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times.Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC (sodium chloride/sodium citrate) and 50% formamide at 55.degree. C., followed by a high-stringency wash consisting of 0.1.times.SSC containing EDTA at 55.degree. C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).

The polynucleotides of this invention can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of skill in the art can use the sequences provided herein and a commercial DNA synthesizer to produce a desired DNA sequence.

For preparing polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotide so amplified can be isolated from the host cell by methods well known within the art. See, e.g., Sambrook et al., 1989.

Alternatively, PCR allows reproduction of DNA sequences. PCR technology is well known in the art and is described in U.S. Pat. Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those of skill in the art, as set forth in Sambrook et al., 1989, supra, for example.

Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial vendors such as BioRad, Strategene, and Invitrogen.

Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the invention. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87/04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.

The vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of introducing vectors or polynucleotides will often depend on features of the host cell.

The invention also provides host cells comprising any of the polynucleotides described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, and CHO cells. See also PCT Publication No. WO 87/04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtillis) and yeast (such as S. cerevisae, S. pombe; or K. lactis). Preferably, the host cells express the cDNAs at a level of about 5 fold higher, more preferably, 10 fold higher, even more preferably, 20 fold higher than that of the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening the host cells for a specific binding to BCMA or an BCMA domain (e.g., domains 1-4) is effected by an immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.

Methods of Using the Bispecific Antibodies

The antibodies (e.g., BCMA, CD3, or bispecific) and the antibody conjugates (e.g., BCMA antibody-drug conjugates) of the present invention are useful in various applications including, but are not limited to, therapeutic treatment methods and diagnostic treatment methods.

In one aspect, the invention provides a method for treating a condition associated with BCMA expression in a subject. In some embodiments, the method of treating a condition associated with BCMA expression in a subject comprises administering to the subject in need thereof an effective amount of a composition (e.g., pharmaceutical composition) comprising the BCMA antibodies or the BCMA antibody conjugates as described herein. The conditions associated with BCMA expression include, but are not limited to, abnormal BCMA expression, altered or aberrant BCMA expression, malignant cells expressing BCMA, and a proliferative disorder (e.g., cancer) or autoimmune disorder.

In another aspect, the invention provides a method for treating a B-cell related cancer or malignant cells expressing a tumor antigen. In some embodiments, provided is a method of treating a B-cell related cancer in a subject in need thereof comprising a) providing the bispecific antibody as described herein, and b) administering said bispecific antibody to said patient. In some embodiments, provided is a method of treating a condition associated with malignant cells expressing a tumor antigen in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising the bispecific antibody as described herein.

Accordingly, in some embodiments, provided is a method of treating a cancer in a subject comprising administering to the subject in need thereof an effective amount of a composition comprising the antibodies (e.g., BCMA, or CD3-BCMA bispecific antibodies) or the BCMA antibody conjugates as described herein. As used herein, cancer can be a B-cell related cancer including, but are not limited to, multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte predominant Hodgkin's lymphoma, Kahler's disease and Myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulienemia, diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmactyic lymphoma, Waldenstrom macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell/histiocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell related lymphoma.

In some embodiments, provided is a method of inhibiting tumor growth or progression in a subject who has malignant cells expressing BCMA, comprising administering to the subject in need thereof an effective amount of a composition comprising the BCMA antibodies, CD3-BCMA bispecific antibodies, or the BCMA antibody conjugates as described herein. In other embodiments, provided is a method of inhibiting metastasis cells expressing BCMA in a subject, comprising administering to the subject in need thereof an effective amount of a composition comprising the BCMA antibodies, CD3-BCMA bispecific antibodies, or the BCMA antibody conjugates as described herein. In other embodiments, provided is a method of inducing tumor regression in malignant cells in a subject, comprising administering to the subject in need thereof an effective amount of a composition comprising the BCMA antibodies, CD3-BCMA bispecific antibodies, or the BCMA antibody conjugates as described herein.

In some embodiments, provided is a method of treating an autoimmune disorder in a subject comprising administering to the subject in need thereof an effective amount of a composition comprising the BCMA antibodies, CD3-BCMA bispecific antibodies, or the BCMA antibody conjugates as described herein.

As used herein, autoimmune disorders include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, diabetes (Type I), multiple sclerosis, Addison's disease, celiac disease, dermatomyositis, Graves' disease, hashimoto's thyroiditis, hashimoto's encephalopathy, Myasthenia gravis, pernicious anemia, reactive arthritis, Sjogren syndrome, acute disseminated encephalomyelitis, agammaglobulinemia, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendorcrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticarial, autoimmune uveitis, Bechet's disease, Castleman's disease, cold agglutinin disease, Crohn's disease, dermatomyositis, eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Guillain-Barre syndrome, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, narcolepsy, pemphigus vulgaris, pernicious anaemia, polymyositis, primary billary cirrhosis, relapsing polychrondritis, rheumatic fever, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

In another aspect, the invention provides an effective amount of a composition (e.g., pharmaceutical composition) comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for treating a condition (e.g., cancer or autoimmune disorder) associated with BCMA expression in a subject in need thereof. In some embodiments, provided is an effective amount of a composition (e.g., pharmaceutical composition) comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inhibiting tumor growth or progression in a subject who has malignant cells expressing BCMA. In some embodiments, provided is an effective amount of a composition (e.g., pharmaceutical composition) comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inhibiting metastasis of malignant cells expressing BCMA in a subject in need thereof. In some embodiments, provided is an effective amount of a composition (e.g., pharmaceutical composition) comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inducing tumor regression in a subject who has malignant cells expressing BCMA.

In another aspect, the invention provides the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for use in treating a condition (e.g., cancer or autoimmune disorder) associated with BCMA expression in a subject in need thereof. In some embodiments, provided is the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inhibiting tumor growth or progression in a subject who has malignant cells expressing BCMA. In some embodiments, provided is the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inhibiting metastasis of malignant cells expressing BCMA in a subject in need thereof. In some embodiments, provided is the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein for inducing tumor regression in a subject who has malignant cells expressing BCMA.

In another aspect, the invention provides a use of the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein in the manufacture of a medicament for treating a condition (e.g., cancer or autoimmune disorder) associated with BCMA expression. In some embodiments, provided is a use of the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting tumor growth or progression. In some embodiments, provided is a use of the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting metastasis of malignant cells expressing BCMA. In some embodiments, provided is a use of the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein in the manufacture of a medicament for inducing tumor regression.

In another aspect, provided is a method of detecting, diagnosing, and/or monitoring a condition associated with BCMA expression. For example, the antibodies (e.g., BCMA or CD3-BCMA bispecific) as described herein can be labeled with a detectable moiety such as an imaging agent and an enzyme-substrate label. The antibodies as described herein can also be used for in vivo diagnostic assays, such as in vivo imaging (e.g., PET or SPECT), or a staining reagent.

In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy is an additional anti-cancer therapy including, but not limited to, chemotherapy, radiation, surgery, hormone therapy, and/or additional immunotherapy.

In some embodiments, the additional form of therapy comprises administering one or more therapeutic agent in addition to the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein. The one or more therapeutic agent can be a chemotherapeutic agents including, but not limited to, a second antibody (e.g., an anti-VEGF (Vascular Endothelial Growth Factor) antibody (e.g., AVASTIN.RTM.), an anti-HER2 antibody (e.g., HERCEPTIN.RTM.), an anti-CD25 antibody, an anti-CD33 antibody, an anti-CD20 antibody (e.g., RITUXAN.RTM.), an anti-mucin-like glycoprotein antibody, an anti-TNF antibody, and/or an epidermal growth factor receptor (EGFR) antibody (e.g., ERBITUX.RTM.)), an angiogenesis inhibitor, a cytotoxic agent (e.g., anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone), taxane (e.g., paclitaxel and docetaxel), dolastatin, duocarmycin, enediyne, geldanamycin, maytansine, puromycin, vinca alkaloid (e.g., vincristine), a topoisomerase inhibitor (e.g., etoposide), tubulysin, a pyrimidine analog (e.g., fluorouracil), platinum-containing agents (e.g., cisplatin, carboplatin, and oxaliplatin), alkylating agents (e.g., melphalan, cyclophosphamide, or carmustine) and hemiasterlin), immunomodulating agent (e.g., prednisone and lenalidomide (REVLIMID.RTM.)), an anti-inflammatory agent (e.g., dexamethasone), an aromatase inhibitor (e.g., anastrozole, exemestane, letrozole, vorozole, formestane, or testolactone), a proteasome inhibitor (e.g., bortezomib such as VELCADE.RTM. ([(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propy- -I]amino]butyl]boronic acid or carfilzomib), and other agents such as tamoxifen.

For example, in some embodiments, provided is a method of treating multiple myeloma comprising administering to a patient need thereof an effective amount of a composition comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein and one or more other therapeutic agent such as a chemotherapeutic agent (e.g., doxorubicin or carfilzomib) or thalidomide or its derivative thereof (e.g., lenalidomide (REVLIMID.RTM.)). In some embodiments, the one or more other therapeutic agent is selecting from the group consisting of bortezomib (e.g., VELCADE.RTM.), melphalan, prednisone, doxorubicin, lenalidomide, thalidomide, prednisone, carmustine, etoposide, cisplatin, cyclophosphamide, carfilzomib, and vincristine. In some embodiments, the other therapeutic agent is bortezomib (e.g., VELCADE.RTM.), melphalan, lenalidomide (REVLIMID.RTM.), carfilzomib, doxorubicin, or prednisone. Accordingly, provided is a method of treating multiple myeloma comprising administering to a patient need thereof an effective amount of a composition comprising the antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein and one or more other therapeutic agent selecting from the group consisting of bortezomib, lenalidomide, carfilzomib, and doxorubicin. In some embodiments, the patient is relapsing or refractory to previous multiple myeloma therapy.

The antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates can be administered to an individual via any suitable route. It should be understood by persons skilled in the art that the examples described herein are not intended to be limiting but to be illustrative of the techniques available. Accordingly, in some embodiments, the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate is administered to an individual in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, intracranial, transdermal, subcutaneous, intra-articular, sublingually, intrasynovial, via insufflation, intrathecal, oral, inhalation or topical routes. Administration can be systemic, e.g., intravenous administration, or localized. Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers are useful for administration. Liquid formulations can be directly nebulized and lyophilized powder can be nebulized after reconstitution. Alternatively, the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate can be aerosolized using a fluorocarbon formulation and a metered dose inhaler, or inhaled as a lyophilized and milled powder.

In one embodiment, the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate is administered via site-specific or targeted local delivery techniques. Examples of site-specific or targeted local delivery techniques include various implantable depot sources of the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate or local delivery catheters, such as infusion catheters, indwelling catheters, or needle catheters, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See, e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No. 5,981,568.

Various formulations of the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate may be used for administration. In some embodiments, the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate may be administered neat. In some embodiments, the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate and a pharmaceutically acceptable excipient may be in various formulations. Pharmaceutically acceptable excipients are known in the art, and are relatively inert substances that facilitate administration of a pharmacologically effective substance. For example, an excipient can give form or consistency, or act as a diluent. Suitable excipients include but are not limited to stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers. Excipients as well as formulations for parenteral and nonparenteral drug delivery are set forth in Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005.

In some embodiments, these agents are formulated for administration by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, etc.). Accordingly, these agents can be combined with pharmaceutically acceptable vehicles such as saline, Ringer's solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual's medical history.

The antibodies (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugates as described herein can be administered using any suitable method, including by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, etc.). The antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate can also be administered via inhalation, as described herein. Generally, for administration of an antibody (e.g., BCMA or CD3-BCMA bispecific) and a BCMA antibody conjugate, an initial candidate dosage can be about 2 mg/kg. For the purpose of the present invention, a typical daily dosage might range from about any of 3 .mu.g/kg to 30 .mu.g/kg to 300 .mu.g/kg to 3 mg/kg, to 30 mg/kg, to 100 mg/kg or more, depending on the factors mentioned above. For example, dosage of about 1 mg/kg, about 2.5 mg/kg, about 5 mg/kg, about 10 mg/kg, and about 25 mg/kg may be used. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved, for example, to inhibit or delay tumor growth/progression or metatstasis of cancer cells. An exemplary dosing regimen comprises administering an initial dose of about 2 mg/kg, followed by a weekly maintenance dose of about 1 mg/kg of the antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugate, or followed by a maintenance dose of about 1 mg/kg every other week. Other exemplary dosing regimen comprises administering increasing doses (e.g., initial dose of 1 mg/kg and gradual increase to one or more higher doses every week or longer time period). Other dosage regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. For example, in some embodiments, dosing from one to four times a week is contemplated. In other embodiments, dosing once a month or once every other month or every three months is contemplated. The progress of this therapy is easily monitored by conventional techniques and assays. The dosing regimen (including the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used) can vary over time.

For the purpose of the present invention, the appropriate dosage of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate will depend on the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate (or compositions thereof) employed, the type and severity of symptoms to be treated, whether the agent is administered for therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, the patient's clearance rate for the administered agent, and the discretion of the attending physician. Typically the clinician will administer an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate until a dosage is reached that achieves the desired result. Dose and/or frequency can vary over course of treatment. Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage. For example, antibodies that are compatible with the human immune system, such as humanized antibodies or fully human antibodies, may be used to prolong half-life of the antibody and to prevent the antibody being attacked by the host's immune system. Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment and/or suppression and/or amelioration and/or delay of symptoms, e.g., tumor growth inhibition or delay, etc. Alternatively, sustained continuous release formulations of antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

In one embodiment, dosages for an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate may be determined empirically in individuals who have been given one or more administration(s) of the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate. Individuals are given incremental dosages of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate. To assess efficacy, an indicator of the disease can be followed.

Administration of an antibody (e.g., BCMA or CD3-BCMA bispecific) or an BCMA antibody conjugate in accordance with the method in the present invention can be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate may be essentially continuous over a preselected period of time or may be in a series of spaced doses.

In some embodiments, more than one antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugate may be present. At least one, at least two, at least three, at least four, at least five different or more antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugate can be present. Generally, those antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates may have complementary activities that do not adversely affect each other. For example, one or more of the following antibody may be used: a first BCMA or CD3 antibody directed to one epitope on BCMA or CD3 and a second BCMA or CD3 antibody directed to a different epitope on BCMA or CD3.

Therapeutic formulations of the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used in accordance with the present invention are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG).

Liposomes containing the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate are prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030, 1980; and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005.

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or `poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT.TM. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Therapeutic antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugate compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

The compositions according to the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween.TM. 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span.TM. 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid.TM., Liposyn.TM., Infonutrol.TM., Lipofundin.TM. and Lipiphysan.TM.. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0 .mu.m, particularly 0.1 and 0.5 .mu.m, and have a pH in the range of 5.5 to 8.0.

The emulsion compositions can be those prepared by mixing an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate with Intralipid.TM. or the components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

Compositions

The compositions used in the methods of the invention comprise an effective amount of an antibody (e.g., BCMA or CD3-BCMA bispecific) or a BCMA antibody conjugate as described herein. Examples of such compositions, as well as how to formulate, are also described in an earlier section and below. In some embodiments, the composition comprises one or more antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates. For example, BCMA antibody or CD3-BCMA bispecific antibody recognizes human BCMA or CD3-BCMA. In some embodiments, the BCMA or CD3-BCMA antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the BCMA antibody or CD3-BCMA antibody comprises a constant region that is capable of triggering a desired immune response, such as antibody-mediated lysis or ADCC. In other embodiments, the BCMA antibody or CD3-BCMA antibody comprises a constant region that does not trigger an unwanted or undesirable immune response, such as antibody-mediated lysis or ADCC.

It is understood that the compositions can comprise more than one antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugate (e.g., a mixture of BCMA antibodies or CD3-BCMA bispecific antibodies that recognize different epitopes of BCMA or CD3 and BCMA). Other exemplary compositions comprise more than one BCMA antibody, CD3-BCMA antibody, or BCMA antibody conjugate that recognize the same epitope(s), or different species of BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA antibody conjugate that bind to different epitopes of BCMA (e.g., human BCMA) or CD3 and BCMA (human CD3 and BCMA).

The composition used in the present invention can further comprise pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and practice of Pharmacy 21st Ed., 2005, Lippincott Williams and Wilkins, Ed. K. E. Hoover), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG). Pharmaceutically acceptable excipients are further described herein.

Kits

The invention also provides kits for use in the instant methods. Kits of the invention include one or more containers comprising the BCMA antibody, CD3-BCMA bispecific antibody, or the BCMA antibody conjugate as described herein and instructions for use in accordance with any of the methods of the invention described herein. Generally, these instructions comprise a description of administration of the BCMA antibody, CD3-BCMA bispecific antibody, or the BCMA antibody conjugate for the above described therapeutic treatments.

The instructions relating to the use of the BCMA antibodies, CD3-BCMA bispecific antibodies, or the BCMA antibody conjugates as described herein generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

The kits of this invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a BCMA antibody, CD3-BCMA bispecific antibody, or a BCMA antibody conjugate. The container may further comprise a second pharmaceutically active agent.

Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.

The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

EXAMPLES

Example 1: Determination of Kinetics and Affinity of hBCMA/Human IgG Interactions at 25.degree. C. and/or 37.degree. C.

This example determines the kinetics and affinity of various anti-BCMA antibodies at 25.degree. C. and 37.degree. C.

All experiments were performed on a Bio-Rad Proteon XPR36 surface Plasmon resonance biosensor (Bio-Rad, Hercules, Calif.). An array of anti-BCMA antibodies was prepared using an amine-coupling method on a Bio-Rad GLC Sensor Chip similar to that described in Abdiche, et al., Anal. Biochem. 411, 139-151 (2011). The analysis temperature for the immobilization was 25.degree. C. and the running buffer was HBS-T+(10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). Channels were activated in the analyte (horizontal) direction by injecting a mixture of 1 mM ECD and 0.25 mM NHS for 3 minutes at a flow rate of 30 .mu.L/min. IgGs were immobilized on the activated spots by injecting them in the ligand (vertical) direction at 20 .mu.g/mL in 10 mM Acetate pH 4.5 buffer for 1.5 minutes at 30 .mu.g/mL. The activated surfaces were blocked by injecting 1M ethanolamine, pH 8.5 in the analyte direction for 3 minutes at 30 .mu.L/min.

The analysis temperature for the hBCMA binding analysis was 37.degree. C. or 25.degree. C. in a running buffer of HBS-T+, supplemented with 1 mg/mL BSA. A kinetic titration method was employed for the interaction analysis as described in Abdiche, et al. The hBCMA (human BCMA) analyte was injected in the analyte direction using a series of injections from low to high concentration. The concentrations used were 0.08 nM, 0.4 nM, 2 nM, 10 nM and 50 nM (a 5-membered series, with a 5-fold dilution factor and top concentration of 50 nM). The association time for a given analyte dilution was two minutes. Immediately after the 50 nM hBCMA injection, dissociation was monitored for 2 hours. Prior to the hBCMA analyte injections, buffer was injected 5 times using the same association and dissociation times at the hBCMA analyte cycles to prepare a buffer blank sensorgram for double-referencing purposes (double referencing as described in Myszka, J. Mol. Recognit. 12, 279-284 (1999).

The sensorgrams were double-referenced and fit to a 1:1 Langmuir with mass transport kinetic titration model in BIAevaluation Software version 4.1.1 (GE Lifesciences, Piscataway, N.J.). The sensorgrams and fits are shown in FIG. 1, and the kinetics and affinity parameters for various anti-BCMA antibodies of the present invention are shown in Tables 6A-6C.

TABLE-US-00012 TABLE 6A t.sub.1/2 Sample k.sub.a (1/Ms) k.sub.d (1/s) (min) K.sub.D (pM) A02_Rd4_6 nM_C01 1.2E+06 2.8E-05 411 24 A02_Rd4_6 nM_C16 1.1E+06 6.2E-05 187 59 Combo_Rd4_0.6 nM_C29 6.6E+06 1.4E-04 83 21 L3PY/H3TAQ 2.6E+06 1.4E-04 84 53

TABLE-US-00013 TABLE 6B T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to huBCMA huBCMA huBCMA huBCMA Antibody @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. P6E01/P6E01 1.04E+06 4.15E-03 2.8 4.0 P6E01/H3.AQ 8.35E+05 3.45E-04 33.53 0.41 L1.LGF/L3.KW/P6E01 8.31E+05 7.55E-03 1.53 9.08 L1.LGF/L3.NY/P6E01 1.33E+06 4.40E-03 2.63 3.32 L1.GDF/L3.NY/P6E01 1.60E+06 5.92E-03 1.95 3.70 L1.LGF/L3.KW/H3.AL 4.28E+05 1.23E-03 9.40 2.87 L1.LGF/L3.KW/H3.AP 9.28E+05 2.27E-03 5.10 2.44 L1.LGF/L3.KW/H3.AQ 5.24E+05 9.56E-04 12.09 1.82 L1.LGF/L3.PY/H3.AP 4.57E+05 9.69E-04 11.92 2.12 L1.LGF/L3.PY/H3.AQ 9.31E+05 8.86E-04 13.04 0.95 L1.LGF/L3.NY/H3.AL 7.63E+05 9.70E-04 11.91 1.27 L1.LGF/L3.NY/H3.AP 9.36E+05 5.33E-04 21.67 0.57 L1.LGF/L3.NY/H3.AQ 6.66E+05 2.99E-04 38.61 0.45 L1.GDF/L3.KW/H3.AL 4.45E+05 3.90E-03 2.96 8.76 L1.GDF/L3.KW/H3.AP 1.17E+06 4.61E-03 2.51 3.93 L1.GDF/L3.KW/H3.AQ 7.97E+05 3.48E-03 3.32 4.37 L1.GDF/L3.PY/H3.AQ 1.42E+06 1.35E-02 0.86 9.49 L1.GDF/L3.NY/H3.AL 9.07E+05 4.03E-03 2.87 4.44 L1.GDF/L3.NY/H3.AP 1.41E+06 1.41E-03 8.21 1.00 L1.GDF/L3.NY/H3.AQ 9.84E+05 7.22E-04 16.00 0.73 L3.KW/P6E01 7.40E+05 3.15E-04 36.66 0.43 L3.PY/P6E01 7.12E+05 2.28E-04 50.74 0.32 L3.NY/P6E01 8.76E+05 3.84E-04 30.08 0.44 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to huBCMA huBCMA huBCMA huBCMA Antibody @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. L3.PY/L1.PS/P6E01 2.49E+06 1.13E-03 10.21 0.45 L3.PY/L1.AH/P6E01 2.55E+06 1.26E-03 9.19 0.49 L3.PY/L1.FF/P6E01 2.39E+06 1.41E-03 8.18 0.59 L3.PY/L1.PH/P6E01 2.81E+06 9.13E-04 12.65 0.32 L3.PY/L3.KY/P6E01 3.18E+06 1.09E-03 10.65 0.34 L3.PY/L3.KF/P6E01 2.88E+06 2.08E-03 5.56 0.72 L3.PY/H2.QR 2.56E+06 1.19E-03 9.75 0.46 L3.PY/H2.DY 2.60E+06 1.38E-03 8.37 0.53 L3.PY/H2.YQ 2.58E+06 1.56E-03 7.41 0.60 L3.PY/H2.LT 2.40E+06 1.29E-03 8.95 0.54 L3.PY/H2.HA 2.43E+06 1.47E-03 7.89 0.60 L3.PY/H2.QL 2.64E+06 2.18E-03 5.31 0.82 L3.PY/H3.YA 3.15E+06 1.18E-03 9.82 0.37 L3.PY/H3.AE 3.29E+06 1.39E-03 8.32 0.42 L3.PY/H3.AQ 3.08E+06 1.73E-03 6.69 0.56 L3.PY/H3.TAQ 3.08E+06 1.14E-03 10.13 0.37 L3.PY/P6E01 2.65E+06 1.96E-03 5.91 0.74 L3.PY/L1.PS/H2.QR 3.97E+06 1.03E-01 0.11 25.85 L3.PY/L1.PS/H2.DY 3.22E+06 3.61E-03 3.20 1.12 L3.PY/L1.PS/H2.YQ 3.35E+06 4.30E-03 2.69 1.28 L3.PY/L1.PS/H2.LT 3.40E+06 4.65E-03 2.49 1.37 L3.PY/L1.PS/H2.HA 3.30E+06 1.06E-02 1.09 3.21 L3.PY/L1.PS/H2.QL 1.52E+07 3.14E-01 0.04 20.64 L3.PY/L1.PS/H3.YA 3.07E+06 9.05E-03 1.28 2.95 L3.PY/L1.PS/H3.AE 3.14E+06 1.46E-03 7.93 0.46 L3.PY/L1.PS/H3.AQ 3.26E+06 1.79E-03 6.46 0.55 L3.PY/L1.PS/H3.TAQ 3.25E+06 2.46E-03 4.70 0.76 L3.PY/L1.AH/H2.QR 3.13E+06 1.81E-03 6.39 0.58 L3.PY/L1.AH/H2.DY 3.05E+06 1.52E-03 7.62 0.50 L3.PY/L1.AH/H2.YQ 2.42E+06 1.93E-03 6.00 0.80 L3.PY/L1.AH/H2.LT 3.16E+06 1.23E-03 9.38 0.39 L3.PY/L1.AH/H2.HA 3.33E+06 1.81E-03 6.37 0.54 L3.PY/L1.AH/H2.QL 3.04E+06 1.60E-03 7.22 0.53 L3.PY/L1.AH/H3.YA 3.00E+06 1.50E-03 7.73 0.50 L3.PY/L1.AH/H3.AE 3.32E+06 1.73E-03 6.70 0.52 L3.PY/L1.AH/H3.AQ 3.03E+06 1.97E-03 5.85 0.65 L3.PY/L1.AH/H3.TAQ 3.27E+06 1.19E-03 9.68 0.37 L3.PY/L1.FF/H2.QR 3.47E+06 1.77E-03 6.54 0.51 L3.PY/L1.FF/H2.DY 4.14E+06 2.71E-03 4.27 0.65 L3.PY/L1.FF/H2.YQ 3.32E+06 1.52E-03 7.61 0.46 L3.PY/L1.FF/H2.LT 3.30E+06 1.67E-03 6.92 0.51 L3.PY/L1.FF/H2.HA 3.49E+06 2.19E-03 5.29 0.63 L3.PY/L1.FF/H2.QL 3.48E+06 1.40E-03 8.28 0.40 L3.PY/L1.FF/H3.YA 3.50E+06 1.80E-03 6.41 0.51 L3.PY/L1.FF/H3.AE 3.82E+06 2.63E-03 4.39 0.69 L3.PY/L1.FF/H3.AQ 3.32E+06 1.54E-03 7.51 0.46 L3.PY/L1.FF/H3.TAQ 3.52E+06 1.89E-03 6.12 0.54 L3.PY/L1.PH/H2.QR 3.69E+06 2.36E-03 4.89 0.64 L3.PY/L1.PH/H2.HA 2.37E+06 1.16E-03 9.99 0.49 L3.PY/L1.PH/H3.AE 3.68E+06 1.34E-03 8.61 0.36 L3.PY/L1.PH/H3.AQ 3.08E+06 1.59E-03 7.27 0.52 L3.PY/L1.PH/H3.TAQ 3.58E+06 2.13E-03 5.43 0.59 L3.PY/L3.KY/H2.QR 2.95E+06 9.90E-04 11.67 0.34 L3.PY/L3.KY/H2.DY 3.19E+06 6.42E-04 18.00 0.20 L3.PY/L3.KY/H2.YQ 2.14E+06 1.65E-03 7.02 0.77 L3.PY/L3.KY/H2.LT 2.92E+06 9.06E-04 12.75 0.31 L3.PY/L3.KY/H2.HA 3.29E+06 1.63E-03 7.10 0.49 L3.PY/L3.KY/H2.QL 3.65E+06 2.08E-03 5.56 0.57 L3.PY/L3.KY/H3.YA 3.30E+06 9.12E-04 12.67 0.28 L3.PY/L3.KY/H3.TAQ 2.79E+06 6.49E-04 17.79 0.23 L3.PY/L3.KF/H2.DY 2.74E+06 1.82E-03 6.35 0.67 L3.PY/L3.KF/H2.YQ 1.96E+06 2.23E-03 5.18 1.14 L3.PY/L3.KF/H2.LT 2.75E+06 1.91E-03 6.05 0.69 L3.PY/L3.KF/H2.QL 2.07E+06 1.25E-03 9.26 0.60 L3.PY/L3.KF/H3.YA 3.12E+06 1.47E-03 7.85 0.47 L3.PY/L3.KF/H3.AE 3.07E+06 1.55E-03 7.44 0.51 L3.PY/L3.KF/H3.AQ 3.48E+06 2.27E-03 5.09 0.65 L3.PY/L3.KF/H3.TAQ 2.82E+06 1.62E-03 7.12 0.58 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to cyBCMA cyBCMA cyBCMA cyBCMA Antibody @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. P6E01/P6E01 7.02E-02 0.16 115.4 P6E01/H3.AQ 1.08E+06 7.40E-03 1.6 6.9 L1.LGF/L3.KW/P6E01 4.55E+05 1.95E-02 0.6 42.8 L1.LGF/L3.NY/P6E01 9.20E+05 1.05E-02 1.1 11.4 L1.GDF/L3.NY/P6E01 1.20E+06 7.67E-03 1.5 6.4 L1.LGF/L3.KW/H3.AL 2.90E+05 1.21E-02 1.0 41.8 L1.LGF/L3.KW/H3.AP 5.54E+05 1.54E-02 0.7 27.8 L1.LGF/L3.KW/H3.AQ 5.27E+05 3.55E-03 3.3 6.7 L1.LGF/L3.PY/H3.AP 3.64E+05 1.30E-02 0.9 35.8 L1.LGF/L3.PY/H3.AQ 1.00E+06 4.77E-03 2.4 4.8 L1.LGF/L3.NY/H3.AL 6.35E+05 1.48E-02 0.8 23.2 L1.LGF/L3.NY/H3.AP 8.30E+05 5.57E-03 2.1 6.7 L1.LGF/L3.NY/H3.AQ 7.51E+05 1.48E-03 7.8 2.0 L1.GDF/L3.KW/H3.AL 3.18E+05 1.80E-02 0.6 56.7 L1.GDF/L3.KW/H3.AP 8.14E+05 2.03E-02 0.6 24.9 L1.GDF/L3.KW/H3.AQ 8.02E+05 5.65E-03 2.0 7.0 L1.GDF/L3.PY/H3.AQ 1.55E+06 1.66E-02 0.7 10.7 L1.GDF/L3.NY/H3.AL 9.00E+05 2.19E-02 0.5 24.3 L1.GDF/L3.NY/H3.AP 1.36E+06 7.02E-03 1.6 5.2 L1.GDF/L3.NY/H3.AQ 1.18E+06 1.36E-03 8.5 1.2 L3.KW/P6E01 7.63E+05 2.57E-03 4.5 3.4 L3.PY/P6E01 8.55E+05 2.93E-03 3.9 3.4 L3.NY/P6E01 1.01E+06 2.87E-03 4.0 2.8 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to cyBCMA cyBCMA cyBCMA cyBCMA Antibody @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. L3.PY/L1.PS/P6E01 2.17E+06 6.06E-03 1.91 2.79 L3.PY/L1.AH/P6E01 2.16E+06 5.72E-03 2.02 2.65 L3.PY/L1.FF/P6E01 2.45E+06 5.91E-03 1.96 2.41 L3.PY/L1.PH/P6E01 2.17E+06 7.89E-03 1.46 3.63 L3.PY/L3.KY/P6E01 2.27E+06 5.02E-03 2.30 2.21 L3.PY/L3.KF/P6E01 2.39E+06 8.30E-03 1.39 3.48 L3.PY/H2.QR 2.18E+06 6.58E-03 1.76 3.02 L3.PY/H2.DY 2.24E+06 6.18E-03 1.87 2.76 L3.PY/H2.YQ 2.46E+06 6.21E-03 1.86 2.53 L3.PY/H2.LT 2.09E+06 7.57E-03 1.53 3.63 L3.PY/H2.HA 1.99E+06 7.55E-03 1.53 3.79 L3.PY/H2.QL 2.05E+06 1.26E-02 0.91 6.16 L3.PY/H3.YA 2.87E+06 5.40E-03 2.14 1.88 L3.PY/H3.AE 2.82E+06 5.04E-03 2.29 1.79 L3.PY/H3.AQ 2.77E+06 5.39E-03 2.14 1.94 L3.PY/H3.TAQ 2.57E+06 4.37E-03 2.64 1.70 L3.PY/P6E01 2.20E+06 1.31E-02 0.88 5.96 L3.PY/L1.PS/H2.QR 5.25E+05 6.70E-04 17.23 1.28 L3.PY/L1.PS/H2.DY 1.90E+06 3.78E-03 3.06 1.99 L3.PY/L1.PS/H2.YQ 2.00E+06 3.74E-03 3.09 1.87 L3.PY/L1.PS/H2.LT 2.17E+06 4.11E-03 2.81 1.89 L3.PY/L1.PS/H2.HA 1.45E+06 2.69E-03 4.30 1.86 L3.PY/L1.PS/H2.QL 6.57E+05 6.36E-04 18.17 0.97 L3.PY/L1.PS/H3.YA 1.77E+06 9.98E-03 1.16 5.65 L3.PY/L1.PS/H3.AE 2.46E+06 4.13E-03 2.80 1.68 L3.PY/L1.PS/H3.AQ 2.52E+06 4.33E-03 2.67 1.72 L3.PY/L1.PS/H3.TAQ 2.58E+06 5.52E-03 2.09 2.14 L3.PY/L1.AH/H2.QR 2.20E+06 4.91E-03 2.35 2.23 L3.PY/L1.AH/H2.DY 2.32E+06 4.51E-03 2.56 1.95 L3.PY/L1.AH/H2.YQ 1.58E+06 4.31E-03 2.68 2.74 L3.PY/L1.AH/H2.LT 2.19E+06 2.96E-03 3.91 1.35 L3.PY/L1.AH/H2.HA 2.58E+06 4.39E-03 2.63 1.70 L3.PY/L1.AH/H2.QL 2.62E+06 9.55E-03 1.21 3.65 L3.PY/L1.AH/H3.YA 2.37E+06 5.26E-03 2.20 2.22 L3.PY/L1.AH/H3.AE 2.25E+06 3.56E-03 3.25 1.58 L3.PY/L1.AH/H3.AQ 2.24E+06 3.99E-03 2.90 1.78 L3.PY/L1.AH/H3.TAQ 2.28E+06 3.02E-03 3.83 1.32 L3.PY/L1.FF/H2.QR 2.55E+06 4.21E-03 2.75 1.65 L3.PY/L1.FF/H2.DY 2.66E+06 5.00E-03 2.31 1.88 L3.PY/L1.FF/H2.YQ 2.19E+06 3.26E-03 3.55 1.49 L3.PY/L1.FF/H2.LT 2.19E+06 3.41E-03 3.38 1.56 L3.PY/L1.FF/H2.HA 2.33E+06 4.17E-03 2.77 1.79 L3.PY/L1.FF/H2.QL 2.36E+06 4.49E-03 2.57 1.91 L3.PY/L1.FF/H3.YA 2.46E+06 4.16E-03 2.77 1.69 L3.PY/L1.FF/H3.AE 2.85E+06 5.01E-03 2.31 1.76 L3.PY/L1.FF/H3.AQ 2.18E+06 3.29E-03 3.51 1.51 L3.PY/L1.FF/H3.TAQ 2.32E+06 3.76E-03 3.07 1.62 L3.PY/L1.PH/H2.QR 2.42E+06 4.36E-03 2.65 1.80 L3.PY/L1.PH/H2.HA 1.61E+06 5.53E-03 2.09 3.44 L3.PY/L1.PH/H3.AE 2.61E+06 2.02E-03 5.72 0.77 L3.PY/L1.PH/H3.AQ 2.28E+06 3.41E-03 3.39 1.50 L3.PY/L1.PH/H3.TAQ 2.51E+06 3.20E-03 3.61 1.28 L3.PY/L3.KY/H2.QR 2.05E+06 7.74E-03 1.49 3.78 L3.PY/L3.KY/H2.DY 1.96E+06 2.43E-03 4.75 1.24 L3.PY/L3.KY/H2.YQ 1.27E+06 2.58E-03 4.47 2.04 L3.PY/L3.KY/H2.LT 1.82E+06 2.32E-03 4.98 1.27 L3.PY/L3.KY/H2.HA 2.28E+06 3.18E-03 3.63 1.40 L3.PY/L3.KY/H2.QL 2.75E+06 4.09E-03 2.83 1.49 L3.PY/L3.KY/H3.YA 1.84E+06 4.28E-03 2.70 2.33 L3.PY/L3.KY/H3.TAQ 1.81E+06 1.92E-03 6.03 1.06 L3.PY/L3.KF/H2.DY 2.08E+06 3.68E-03 3.14 1.77 L3.PY/L3.KF/H2.YQ 1.41E+06 5.01E-03 2.30 3.55 L3.PY/L3.KF/H2.LT 1.91E+06 4.13E-03 2.80 2.16 L3.PY/L3.KF/H2.QL 1.42E+06 3.10E-03 3.73 2.18 L3.PY/L3.KF/H3.YA 2.10E+06 7.96E-03 1.45 3.78 L3.PY/L3.KF/H3.AE 1.85E+06 5.64E-03 2.05 3.05 L3.PY/L3.KF/H3.AQ 2.55E+06 2.38E-03 4.85 0.93 L3.PY/L3.KF/H3.TAQ 2.01E+06 1.91E-03 6.05 0.95

TABLE-US-00014 TABLE 6C* Human Cyno Antibody ka (1/Ms) kd (1/s) KD (pM) ka (1/Ms) kd (1/s) KD (pM) P5A2_VHVL 6.96E+06 3.87E-02 5567 1.61E+06 1.64E-02 10230 A02_Rd4_0.6 nM_C06 3.49E+06 7.37E-05 21 1.81E+06 1.05E-04 58 A02_Rd4_0.6 nM_C09 5.50E+06 9.75E-05 18 2.13E+06 1.74E-04 82 A02_Rd4_6 nM_C16 1.56E+06 1.41E-04 90 1.34E+06 1.58E-04 118 A02_Rd4_6 nM_C03 1.69E+06 1.26E-04 75 1.17E+06 1.85E-04 158 A02_Rd4_6 nM_C01 3.11E+06 9.20E-05 30 1.45E+06 5.83E-04 401 A02_Rd4_6 nM_C26 4.26E+06 1.39E-04 33 2.21E+06 4.48E-04 203 A02_Rd4_6 nM_C25 2.75E+06 1.80E-04 65 1.50E+06 3.30E-04 220 A02_Rd4_6 nM_C22 3.38E+06 1.82E-04 54 1.84E+06 3.24E-04 176 A02_Rd4_6 nM_C19 3.00E+06 1.48E-04 49 2.54E+06 6.61E-04 260 A02_Rd4_0.6 nM_C03 4.27E+06 1.82E-04 43 2.12E+06 4.26E-04 201 A02_Rd4_6 nM_C07 1.48E+06 1.89E-04 128 6.91E+05 7.86E-04 1138 A02_Rd4_6 nM_C23 1.22E+07 2.55E-04 21 2.63E+06 4.14E-04 157 A02_Rd4_0.6 nM_C18 4.73E+06 2.29E-04 48 3.24E+06 6.39E-04 197 A02_Rd4_6 nM_C10 4.51E+06 3.15E-04 70 1.90E+06 8.98E-04 472 A02_Rd4_6 nM_C05 3.10E+06 3.08E-04 99 1.36E+06 1.29E-03 950 A02_Rd4_0.6 nM_C10 2.30E+06 2.96E-04 129 8.83E+05 1.63E-03 1842 A02_Rd4_6 nM_C04 4.47E+06 6.03E-04 135 2.18E+06 8.31E-04 381 A02_Rd4_0.6 nM_C26 7.26E+06 4.43E-04 61 2.71E+06 2.56E-03 941 A02_Rd4_0.6 nM_C13 8.53E+06 5.66E-04 66 2.29E+06 1.28E-03 560 A02_Rd4_0.6 nM_C01 4.74E+06 9.15E-04 193 2.39E+06 1.57E-03 655 A02_Rd4_6 nM_C08 3.92E+06 7.38E-04 188 2.23E+06 1.13E-02 5072 P5C1_VHVL 1.16E+07 6.92E-02 5986 3.53E+06 5.38E-02 15231 C01_Rd4_6 nM_C24 7.47E+06 3.48E-03 467 3.17E+06 8.91E-04 281 C01_Rd4_6 nM_C26 1.50E+07 1.36E-03 90 4.75E+06 1.99E-03 419 C01_Rd4_6 nM_C02 1.61E+07 1.44E-03 89 5.12E+06 2.18E-03 426 C01_Rd4_6 nM_C10 1.31E+07 2.12E-03 162 4.44E+06 2.19E-03 493 C01_Rd4_0.6 nM_C27 1.23E+07 3.74E-03 303 3.34E+06 2.85E-03 852 C01_Rd4_6 nM_C20 6.02E+06 2.76E-03 459 3.60E+06 6.25E-03 1737 C01_Rd4_6 nM_C12 1.21E+07 6.49E-03 535 4.51E+06 3.70E-03 820 C01_Rd4_0.6 nM_C16 1.55E+07 6.30E-03 407 4.95E+06 4.64E-03 939 C01_Rd4_0.6 nM_C09 1.51E+07 8.25E-03 545 5.28E+06 9.36E-03 1773 C01_Rd4_6 nM_C09 1.58E+07 1.28E-02 811 3.73E+06 8.68E-03 2328 C01_Rd4_0.6 nM_C03 1.55E+07 1.50E-02 964 4.72E+06 1.19E-02 2528 C01_Rd4_0.6 nM_C06 1.82E+07 1.54E-02 847 6.22E+06 1.21E-02 1948 C01_Rd4_6 nM_C04 2.33E+07 4.97E-02 2134 6.34E+06 3.27E-02 5156 COMBO_Rd4_0.6 nM_C22 1.97E+06 7.15E-05 36 1.34E+06 6.66E-05 50 COMBO_Rd4_6 nM_C21 1.17E+07 7.34E-05 6 3.17E+06 2.48E-04 78 COMBO_Rd4_6 nM_C10 5.47E+06 9.72E-05 18 1.52E+06 1.60E-04 105 COMBO_Rd4_0.6 nM_C04 1.07E+07 1.58E-04 15 3.52E+06 1.37E-04 39 COMBO_Rd4_6 nM_C25 7.98E+06 1.13E-04 14 2.85E+06 2.26E-04 79 COMBO_Rd4_0.6 nM_C21 1.34E+07 1.15E-04 9 3.63E+06 3.04E-04 84 COMBO_Rd4_6 nM_C11 6.74E+06 1.24E-04 18 2.64E+06 4.12E-04 156 COMBO_Rd4_0.6 nM_C20 7.65E+06 1.46E-04 19 3.09E+06 2.84E-04 92 COMBO_Rd4_6 nM_C09 8.85E+06 1.43E-04 16 2.37E+06 3.18E-04 134 COMBO_Rd4_6 nM_C08 8.99E+06 1.69E-04 19 3.06E+06 4.28E-04 140 COMBO_Rd4_0.6 nM_C19 7.86E+06 1.55E-04 20 2.92E+06 9.79E-04 336 COMBO_Rd4_0.6 nM_C02 8.57E+06 1.85E-04 22 3.01E+06 4.94E-04 164 COMBO_Rd4_0.6 nM_C23 7.39E+06 2.10E-04 28 2.81E+06 5.31E-04 189 COMBO_Rd4_0.6 nM_C29 1.47E+07 2.77E-04 19 4.00E+06 3.36E-04 84 COMBO_Rd4_0.6 nM_C09 1.04E+07 3.19E-04 31 3.77E+06 3.46E-04 92 COMBO_Rd4_6 nM_C12 1.38E+07 2.70E-04 20 3.29E+06 4.86E-04 148 COMBO_Rd4_0.6 nM_C30 4.35E+06 2.82E-04 65 1.68E+06 8.08E-04 481 COMBO_Rd4_0.6 nM_C14 8.66E+06 3.28E-04 38 3.48E+06 6.45E-04 185 COMBO_Rd4_6 nM_C07 1.05E+07 3.71E-04 35 3.94E+06 9.34E-04 237 COMBO_Rd4_6 nM_C02 1.05E+06 4.43E-04 422 7.95E+05 1.36E-03 1714 COMBO_Rd4_0.6 nM_C05 4.32E+06 4.97E-04 115 1.94E+06 1.72E-03 886 COMBO_Rd4_0.6 nM_C17 8.68E+06 8.01E-04 92 3.06E+06 1.01E-03 330 COMBO_Rd4_6 nM_C22 3.03E+06 7.75E-04 256 1.70E+06 1.65E-03 972 COMBO_Rd4_0.6 nM_C11 5.11E+06 1.06E-03 207 2.20E+06 4.23E-03 1924 *The binding analysis was conducted at 37.degree. C.

Example 2: Flow Cytometry of Human Anti-BCMA Antibodies on BCMA Positive Tumor Cells

This example demonstrates binding of BCMA positive tumor cells by various BCMA antibodies of the present invention.

Binding of human anti-hBCMA expressed in mouse IgG2a were assessed on BCMA-expressing cells (KMS12BM, L363, MM1S and KMS12PE) by flow cytometry. 250,000 cells were incubated with 0.5 ug antibody in 100 uL binding buffer (PBS (Phosphate Buffered Saline)+0.2% BSA (Bovine Serum Albumin)), followed by incubation with Alex Fluor 647 conjugated anti-mouse IgG (Biolegend). Table 7 shows MFI (mean fluorescence intensity) on BCMA positive tumor cells by various BCMA antibodies (e.g., Combo_Rd4_0.6 nM_C29, A02_Rd4_6 nM_C01, A02_Rd4_6 nM_C16, and P6E01/H3TAQ)

TABLE-US-00015 TABLE 7 Combo_Rd4_0.6 A02_Rd4_6 A02_Rd4_6 P6E01/ secondary only nM_C29 nM_C01 nM H3TAQ Cell Line MFI KMS12PE (BCMA+++) 26 6114 5862 3094 6018 MM1S (BCMA++) 22 2569 2539 1951 2715 L363 (BCMA+) 22 1667 1176 789 1457 KMS12BM (BCMA+) 22 583 580 421 634

Example 3: Cytotoxicity of Anti-BCMA ADCs in BCMA Positive Cells

This example illustrates the efficacy of the anti-BCMA ADCs in BCMA positive cells.

Human anti-BCMA (L3.PY/P6E01, L3.PY/H3.TAQ, Combo_Rd4_0.6 nM_C29, A02_Rd4_6 nM_C01, and A02_Rd4_6 nM_C16) antibodies were expressed as human IgG1 subtypes engineered with glutamine-containing transglutaminase ("Q") tags (e.g. LCQ05, H7c, N297A, N297Q, N297A/H7c, N297Q/LCQ05) for drug antibody ratios (DAR) of 2, 4, and 6. TG17 corresponds to SEQ ID NO: 472 (LLQGPP); LCQ05 correspond to SEQ ID NO: 474 (GGLLQGPP), H7c correspond to SEQ ID NO: 454 (LLQG), respectively, and conjugated with AcLys-Val-Cit-PABC-Aur0101 (Acetyl-Lysine-Valine-Citrulline-p-aminobenzyloxycarbonyl), amino-PEG6-C2-Aur3377, or amino-PEG6-C2-Aur0131 as indicated in Table 8. In one instance, the transglutaminase tags can be engineered at the light chain, heavy chain, or a combination of light and heavy chains. In other instance, the transglutaminase tag (e.g., Q) is engineered at site of the antibody, such as at position 297 of the human IgG (EU numbering scheme). For example, the wild-type amino acid asparagine (N) is substituted with glutamine or alanine at position 297 of the BCMA antibody (N297Q or N297A) of the present invention. Anti-BCMA antibody conjugation to Aur0101, Aur3377, and Aur0131 was then achieved via microbial transglutaminase-catalyzed transamidation reaction between the anti-BCMA antibody carrying a targeted glutamine or glutamine tag at the specific site (e.g., carboxyl terminus or amino terminus of the heavy chain or light chain, position 297, or at another site of the antibody) and an amine-containing derivative of the payload (e.g., MMAD, Aur0101, Aur3377, or Aur0131). In some instances, the wild-type amino acid lysine at position 222, 340, or 370 (in accordance with EU numbering scheme) was replaced with amino acid arginine ("K222R", "K340R", or "K370R"). For example, the K222R substitution was found to have the surprising effect of resulting in more homogenous antibody and payload conjugate, better intermolecular crosslinking between the antibody and the payload, and/or significant decrease in interchain crosslinking with the glutamine tag on the C-terminus of the antibody light chain.

In the transamidation reaction, the glutamine on the antibody acted as an acyl donor, and the amine-containing compound acted as an acyl acceptor (amine donor). Purified anti-BCMA antibody in the concentration of 1-150 .mu.M was incubated with a 5-100 molar excess acyl acceptor, ranging between 5 .mu.M-15 mM, in the presence of 0.23-0.55% (w/v) Streptoverticillium mobaraense transglutaminase (ACTIVA.TM., Ajinomoto, Japan) in 10-1000 mM NaCl, and 25 mM MES, HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] or Tris HCl buffer at pH range 6.2-8.8. The reaction conditions were adjusted for individual acyl acceptor derivatives, and the optimal efficiency and specificity were typically observed for 33 .mu.M antibody, 0.67 mM derivative, and 0.378% (w/v) transglutaminase in 75 mM NaCl, 25 mM Tris HCl, pH 8.5. Following incubation at 20-37 deg C. for 1-24 hours, the antibody was purified on Butyl Sepharose High Performance (Butyl HP) resin (GE Healthcare, Waukesha, Wis.) using standard chromatography methods known to persons skilled in the art, such as commercial hydrophobic interaction chromatography from GE Healthcare.

Target expressing (MM1.S, KMS12BM and L363) cells were then seeded on clear bottom plates at 3000 cells/well. Cells were treated with 4-fold serially diluted antibody-drug conjugates in triplicates. Cell viability was determined by CellTiter-Glo.RTM. Luminescent Cell Viability Assay 96 (Promega, Madison Wis.) 96 hours after treatment. Relative cell viability was determined as percentage of untreated control. EC50 was calculated by Prism software. Table 8 shows that all human anti-BCMA antibodies of the present invention conjugated to cytotoxic agent 0101, 3377, and 0131 through transglutaminase tags and linkers exert potent cell killing activity in BCMA expressing cells.

TABLE-US-00016 TABLE 8 EC50 MM1.S LUCGFP (BCMA++) KMS12BM LUCGFP (+) L363 LUCGFP (+) ANTIBODY DAR nM ug/mL nM ug/mL nM ug/mL L3.PY/P6E01 4 0.42 0.06 31.79 4.77 7.34 1.10 N297Q/K222R AcLys vc0101 L3PY/H3.TAQ 4 0.12 0.02 3.94 0.59 0.60 0.09 N297Q/K222R Aclys vc0101 A02_Rd4_6nM_C01 3.91 0.26 0.04 18.67 2.80 2.53 0.38 N297Q/K222R Aclys vc0101 A02_Rd4_6nM_C16 3.92 0.80 0.12 38.73 5.81 9.68 1.45 N297Q/K222R Aclys vc0101 Combo_Rd4_0.6nM_C29 2 0.13 0.02 10.91 1.64 1.67 0.25 LCQ05/K222R Aclys vc0101 Combo_Rd4_0.6nM_C29 3.9 0.11 0.02 0.99 0.15 0.66 0.10 N297Q/K222R Aclys vc0101 Combo_Rd4_0.6nM_C29 5.98 0.34 0.05 1.19 0.18 1.05 0.16 LCQ05/N297Q/K222R Aclys vc0101 Combo_Rd4_0.6nM_C29 3.81 0.23 0.03 0.85 0.13 0.81 0.12 H7c/N297A/K222R AmPEG6 Aur0131 Combo_Rd4_0.6nM_C29 3.88 0.30 0.05 5.01 0.75 1.36 0.20 H7c/N297A/K222R AmPEG6 Aur3377

Example 4: Anti-BCMA ADCs Induce Tumor Regression in an Orthotopic Multiple Myeloma Model

This example illustrates the in vivo efficacy of the anti-BCMA ADCs in the MM1S orthotopic multiple myeloma model.

In vivo efficacy study of BCMA ADCs was performed with multiple myeloma cell line MM1.S expressing luciferase and GFP (Green Fluorescent Protein) in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female CB17/SCID animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enable monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 1-3E6 for all animals, the animals were randomized into groups and a single dose of a human anti-BCMA antibody conjugated with 1) LCQ05/K222R-vc0101 at the C-terminus of the antibody light chain and control conjugates were administered through bolus tail vein injection. Animals were terminated when they exhibit hindlimb paralysis, an endpoint for MM1.S orthotopic models. FIG. 2 shows that a single dose at 3 mg/kg of various human anti-BCMA ADCs inhibits tumor progression as compared to the negative control (NNC), including P6E01/P6E01-AcLys-Val-Cit-PABC-Aur0101; P5A2_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5C1_VHVL-AcLys-Val-Cit-PABC-Aur0101; P4G4-AcLys-Val-Cit-PABC-Aur0101; and P1A11-AcLys-Val-Cit-PABC-Aur0101.

This study demonstrates that treatment with a BCMA-ADC inhibits progression of multiple myeloma.

Example 5: Anti-BCMA ADCs Induce Tumor Regression and Inhibition in an Orthotopic Multiple Myeloma Model

This example also illustrates the in vivo efficacy of the anti-BCMA ADCs in the MM1.S orthotopic multiple myeloma models.

In vivo efficacy study of BCMA ADCs was performed with multiple myeloma cell line MM1.S expressing luciferase and GFP in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female CB17/SCID animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enable monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 1-3E6 for all animals, the animals were randomized into groups; 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101, and 6) control conjugate LCQ04/K222R-AcLys-Val-Cit-PABC-Aur0101. A single dose of human anti-BCMA ADCs and control conjugate were administered through bolus tail vein injection. Animals were terminated when they exhibit hindlimb paralysis, an endpoint for MM1.S orthotopic model. FIG. 3 shows that a single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated with 1) H7c/N297A/K222R-amino-PEG6-C2-0131 and 2) H7c/N297A/K222R-amino-PEG6-C2-3377 resulted in tumor regression. A single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated with 1) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 2) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, and 3) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101 resulted in tumor inhibition.

Accordingly, this study demonstrates that treatment with a BCMA-ADC induces regression and inhibits progression of multiple myeloma.

Example 6: Anti-BCMA ADCs Induce Tumor Inhibition in an Orthotopic Multiple Myeloma Model

This example also illustrates the in vivo efficacy of the anti-BCMA ADCs in the KMS12BM orthotopic multiple myeloma models

In vivo efficacy study of BCMA ADCs was performed with multiple myeloma cell line KMS12BM expressing luciferase and GFP in an orthotopic model. 6-8 weeks old female NSG animals were irradiated with 100cGy and 24 hours post irradiation, ten million KMS12BM LucGFP cells were injected intravenously through the tail vein. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enable monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin are captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 5E6 for all animals, the animals were randomized into groups; 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur010, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101, and 6) control conjugate LCQ04/K222R-AcLys-Val-Cit-PABC-Aur0101. A single dose of human anti-BCMA ADCs and control conjugate was administered through bolus tail vein injection. Animals were terminated when they lose more than 15% of total body weight, an endpoint for KMS12BM orthotopic models. FIG. 4 shows that a single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated with 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101 resulted in tumor inhibition.

Accordingly, this study further demonstrates that treatment with a BCMA-ADC induces regression and inhibits progression of multiple myeloma.

Example 7: Dose Response Curve of Anti-BCMA ADC in MM1S Orthotopic Model

This example further illustrates the in vivo efficacy of the anti-BCMA ADCs in the MM1S orthotopic multiple myeloma models

In vivo efficacy study of BCMA ADCs was performed with multiple myeloma cell line MM1.S expressing luciferase and GFP in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female CB17/SCID animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enable monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 1.2E6 for all animals, the animals were randomized into groups; 1) 0.1 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, 2) 0.38 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, 3) 0.75 mg/kg H7c/N297A/K222-amino-PEG6-C2-0131, 4) 1.5 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) 3 mg/kg control conjugate N297Q/K222R-AcLys-VC-0101. A single dose of human anti-BCMA ADCs and control conjugate were administered through bolus tail vein injection. Animals were terminated when they exhibit hindlimb paralysis, an endpoint for MM1.S orthotopic model. FIG. 5 shows that a single dose of human anti-BCMA COMBO_Rd4_0.6 nM_C29 antibody conjugated with groups 1)-4) above resulted in tumor regression starting at 0.1 mg/kg and tumor inhibition up to 100 days starting at 0.75 mg/kg.

Accordingly, this study demonstrates that treatment with a BCMA-ADC induces tumor regression and tumor inhibition in multiple myeloma.

Example 8: Generation and Purification of Heterodimeric Antibodies

This example describes the generation and purification of the heterodimeric antibodies of the present application.

The variable region of the human specific anti-CD3 antibody was cloned into a human IgG1 or IgG2AA containing the following mutations 221R, 228R, and K409R; or 223R, 225R, 228R, and K409R, respectively, and referred as hlgG1 RRR or IgG2.DELTA.A-RRRR.

The variable region of the anti-target antibody was cloned into a human IgG1 or IgG2.DELTA.A containing the following mutations 221E, 228E, L368E or 223E, 225E, 228E and L368E, respectively, and referred as hlgG1EEE or hlgG2.DELTA.A-EEEE.

Heterodimers were prepared by incubation of the anti-CD3 IgG1 or IgG2.DELTA.A having hlgG1 RRR or IgG2.DELTA.A-RRRR mutations with an anti-target antibody having hlgG1EEE or hlgG2.DELTA.A-EEEE mutations in PBS with 1 mM or 2 mM GSH for 24 hrs at 37.degree. C. as described in International Patent Application No. PCT/US2011/036419 (WO2011/143545). The heterodimer was purified by ion exchange chromatography, as described below.

All the heterodimers were purified by ion exchange chromatography. Briefly, analytical ion exchange separation of the Fc-hetero and Fc-homodimers was carried out on Agilent 1100 quaternary pump LC system (Agilent Inc, Santa Clara, Calif., USA) equipped with weak cation exchange DIONEX Propac WCX-10G (4.times.50 mm) column. Proteins were injected in 5% buffer A (20 mM MES pH 5.4) and eluted in a gradient from 25% to 75% buffer B (20 mM MES pH 5.4 and 500 mM NaCl) over a 20 minute period with 1 ml/min flow rate. Larger scale Fc-heterodimer purification was performed on an Akta Explorer (GE) equipped with weak cation exchange DIONEX Propac WCX-10G (4.times.250 mm) column. Proteins were injected in 5% buffer A (20 mM MES pH 5.4) and eluted in a gradient from 15% to 75% buffer B (20 mM MES pH 5.4 and 500 mM NaCl) over a 60 minute period with 1 ml/min flow rate.

Example 9: Determination of Kinetics and Affinity of hCD3/Human IgG Interactions at 25.degree. C. and/or 37.degree. C.

This example determines the kinetics and affinity of various anti-CD3 antibodies at 25.degree. C. and 37.degree. C.

All experiments were performed on a Bio-Rad Proteon XPR36 surface Plasmon resonance biosensor (Bio-Rad, Hercules, Calif.). An array of anti-CD3 antibodies was prepared using an amine-coupling method on a Bio-Rad GLC Sensor Chip similar to that described in Abdiche, et al., Anal. Biochem. 411, 139-151 (2011). The analysis temperature for the immobilization was 25.degree. C. and the running buffer was HBS-T+ (10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). Channels were activated in the analyte (horizontal) direction by injecting a mixture of 1 mM ECD and 0.25 mM NHS for 3 minutes at a flow rate of 30 .mu.L/min. IgGs were immobilized on the activated spots by injecting them in the ligand (vertical) direction at 20 .mu.g/mL in 10 mM Acetate pH 4.5 buffer for 1.5 minutes at 30 .mu.g/mL. The activated surfaces were blocked by injecting 1M ethanolamine, pH 8.5 in the analyte direction for 3 minutes at 30 .mu.L/min.

The analysis temperature for the hCD3 binding analysis was 37.degree. C. or 25.degree. C. in a running buffer of HBS-T+, supplemented with 1 mg/mL BSA. A kinetic titration method was employed for the interaction analysis as described in Abdiche, et al. The hCD3 (human CD3) analyte was injected in the analyte direction using a series of injections from low to high concentration. The concentrations used were 0.08 nM, 0.4 nM, 2 nM, 10 nM and 50 nM (a 5-membered series, with a 5-fold dilution factor and top concentration of 50 nM). The association time for a given analyte dilution was two minutes. Immediately after the 50 nM hCD3 injection, dissociation was monitored for 2 hours. Prior to the hCD3 analyte injections, buffer was injected 5 times using the same association and dissociation times at the hCD3 analyte cycles to prepare a buffer blank sensorgram for double-referencing purposes (double referencing as described in Myszka, J. Mol. Recognit. 12, 279-284 (1999).

The sensorgrams were double-referenced and fit to a 1:1 Langmuir with mass transport kinetic titration model in BIAevaluation Software version 4.1.1 (GE Lifesciences, Piscataway, N.J.). The kinetics and affinity parameters for various anti-CD3 antibodies of the present invention are shown in Table 9.

TABLE-US-00017 TABLE 9 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to huCD3ed huCD3ed huCD3ed huCD3ed Antibody @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. H2B4 3.7E+05 2.0E-03 5.8 5.3 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to huCD3ed huCD3ed huCD3ed huCD3ed Antibody @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. @ 37.degree. C. H2B4 4.37E+05 0.01369 0.84 3.14E-08 h2B4-VH-wt VL_TK 3.80E+05 1.40E-02 0.83 3.80E-08 h2B4-VH-Hnps VL_TK 3.90E+05 1.60E-02 0.72 4.10E-08 h2B4-VH-yads VL_TK 2.40E+05 2.10E-02 0.79 8.60E-08 h2B4-VH-yaes VL_TK 2.30E+05 2.30E-02 0.50 1.00E-07 h2B4-VH-yaps VL_TK 2.50E+05 2.30E-02 0.50 9.20E-08 T 1/2 (min) KD (nM) ka (1/Ms) kd (1/s) to to cyCD3ed cyCD3ed cyCD3ed cyCD3ed Antibody @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. @ 25.degree. C. H2B4 3.9E+05 1.5E-03 7.7 3.8

Example 10: Flow Cytometry of Human Anti-CD3 Bispecific Antibodies on B Cells and CD8+ T Cells

This example demonstrates the efficacy of the anti-CD3-anti-CD20 bispecific antibodies in CD20+ cells.

Cynomolgus monkey studies were conducted at Charles River Laboratories, Preclinical Services Nevada in accordance with the Institutional Animal Care and Use Committee. Animals (n=2) were dosed via intravenous bolus injection with the bispecific anti-CD20/h2B4 antibody at doses of 500 ug/kg, 100 ug/kg, 20 ug/kg, 2 ug/kg, 0.2 ug/kg or 0.02 ug/kg. Animals were observed twice daily and at each blood collection time point. Blood for flow cytometry and cytokine analysis was collected into K2EDTA tubes from a peripheral vessel not used for i.v. dosing.

Efficacy was determined by measuring B cells and T cells in peripheral blood by flow cytometry. Whole blood was collected at the time points indicated and kept at 4.degree. C. until analysis. Erythrocytes were lysed with ACK buffer (Gibco) for 5 minutes at room temperature and white blood cells were pelleted by centrifugation. Cells were stained for 1 hr. at 4.degree. C. with a cocktail containing fluorescently labeled antibodies recognizing cyno CD19 (Beckman Coulter), CD45, CD4, CD8, Ki67 (BD Biosciences) in PBS+2% FBS. For Ki67 analysis, cells were first stained with CD4 and CD8, then fix/permeabilized with BD cyotfix/cytoperm kit (BD Biosciences) according to manufacturer's instructions prior to intracellular staining for Ki67. Acquisition of cells on a BD LSRII flow cytometer was carried out immediately after staining.

The resulting B cell count was graphed as a percentage of the pre-study B cell count in FIGS. 6A-6F. Prolonged B cell depletion following a single dose was achieved with doses as low as 2 ug/kg. B cell depletion was seen at all doses. The duration of the depletion effect was dose dependent.

The resulting CD8+ T cell count was graphed as percentage of the pre-study CD8+ T cell count in FIGS. 7A-7F. After an initial relocalization, T cell levels were restored to baseline levels or above for the duration of the study.

Example 11: Flow Cytometry of Human Anti-CD3 Bispecific Antibodies on CD8+ T Cells

This example demonstrates the efficacy of the monovalent anti-CD3 antibody on T cell kinetics and activation.

Cynomolgus monkey studies were conducted and efficacy was determined by measuring T cells in peripheral blood by flow cytometry as described in Example 3. Cynomolgus monkeys (n=2) were dosed weekly, i.v., at 0.2 ug/kg with anti-CD20/h2B4 or NNC (non-specific antibody)/h2B4. In contrast to the CD20 targeted bispecific antibody, the NNC/h2B4 has little to no effect on CD8+ T cell kinetics in the blood as measured by flow cytometry. Ki67 was used as a marker for T cell activation.

The resulting T cell count was graphed as percentage of the pre-study CD8+ T cell count in FIGS. 8A and 8B. In cynomolgus monkeys dosed with the CD20/h2B4 bispecific antibody, Ki67+ T cells increased and peaked between day 3 and day 7 post dose, indicating T cell activation. However, in cynomolgus monkeys dosed with NNC/h2B4, there was no increase in Ki67+ T cells.

Example 12: Flow Cytometry of Human Anti-CD3 Bispecific Antibodies on B Cells

This example demonstrates the effect of anti-CD3 arm affinity on B cell depletion.

Cynomolgus monkey studies were conducted and efficacy was determined by measuring T cells in peripheral blood by flow cytometry as described in Example 10. Bispecific antibodies were made with an anti-CD20 arm paired with 4 anti-CD3 antibody arms with different affinities. Following a single, i.v. dose at 0.2 ug/kg, efficacy was determined by measuring B cells in peripheral blood by flow cytometry.

In FIGS. 9A-9D, the resulting B cell count was graphed as a percentage of the pre-study B cell count. Efficacy of B cell depletion correlates to anti-CD3 arm affinity.

Example 13: In Vitro Study of the Bispecific Antibody on T-Cell Mediated Killing of BCMA Positive Cells

This example illustrates the in vitro cytotoxicity of the Anti-BCMA/CD3 hlgG2.DELTA.A Bispecific in BCMA Positive Cells.

Human anti-BCMA (P5A2, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C16, P5C1, C01_Rd4_6 nM_C12, COMBO_Rd4_0.6 nM_C22, Combo_Rd4_0.6 nM_C29, L3PY/H3TAQ and A02_Rd4_6 nM_C01) and human anti-CD3 (H2B4) antibodies were expressed as human IgG2dA engineered with EEEE for bispecific exchange as described in Example 8.

CD3+ T cells from PBMC were negatively selected using Pan T Cell Isolation kit, human (Miltenyi, San Diego Calif.). Target expressing (KMS12PE, L363 and Molp8) cells and CD3+ T-cells were seeded on clear U-bottom plates at 20000 and 100000 cells/well respectively. Cells were treated with 10-fold serially diluted bispecific antibody in triplicates. Cell death was determined by CytoTox 96.RTM. Non-Radioactive Cytotoxicity Assay (Promega, Madison Wis.) 20 hours after treatment. Cell cytotoxicity was determined as percentage of untreated effector plus target control wells. EC50 was calculated by Prism software. Table 10 shows that all human anti-BCMA_H2B4 bispecific antibodies exert cell killing activity in BCMA expressing cells.

TABLE-US-00018 TABLE 10 KMS12PE KMS12BM MOLP8 Anti-BCMA bispecific (BCMA+++) (BCMA+) (MOLP8+) P5A2 0.371 1.509 5.231 A02_Rd4_0.6 nM_C01 0.073 0.078 0.550 A02_Rd4_6 nM_C16 0.186 0.052 0.315 P5C1 0.581 4.117 N/A C01_Rd4_6 nM_C12 0.189 0.415 0.850 COMBO_Rd4_0.6 nM_C22 0.115 0.049 0.065 Combo_Rd4_0.6 nM_C29 0.175 0.049 0.201 L3PY/H3TAQ 0.070 0.055 0.337 A02_Rd4_6 nM_C01 UND 0.057 0.060 UND is undetermined; N/A is EC50 could not be determined.

Example 14: In Vitro Characterization of the Mouse Hybridoma Cloned Anti-CD3 Antibody

This example illustrates the in vitro T cell activation/proliferation of the anti-CD3 cloned from mouse hybridoma in human/cynomolgus PBMC cells for antibody screening.

Human anti-CD3 antibodies were cloned from immunized mouse, expressed as mouse IgG1, and purified by Protein A affinity beads. Human/Cynomolgus peripheral blood mononuclear cells (hu/cyPBMC) were prepared by Ficoll (Density: 1.083 g/mL, GE) density gradient centrifugation from blood filters obtained from local blood banks. Erythrocytes were removed by incubating in LCK buffer (155 mM NH4Cl, 10 mM KHCO3, 100 mM EDTA; Gibco) for 3 minutes at room temperature. Cells were centrifuged for 5 min at 600 g. The supernatant containing the lysed erythrocytes was discarded, and the PBMC were washed twice in 50 ml 1.times.PBS/1% BSA/1 mM EDTA. The pelleted cells were adjusted to 10.sup.7 cells per ml in culture media, X-VIVO-15, serum free media (Lonza), and the PBMC were seeded as 10.sup.6 (100 ul) per-well to round bottom 96 well tissue culture plates. Selected Abs are 10.times. serial diluted from 1000 ng to Ing per mL for mixing with human PBMC and 5.times. serial diluted from 5000 ng to 200 ng per mL for mixing with cynomolgus PBMC. For analysis of PBMC T cell proliferation by .sup.3H-thymidine incorporation, 2 day cultures were performed in triplicate. During the final 16 h of culture .sup.3H-thymidine (0.5 mCi/well) was added, and incorporation was measured. Cells are harvested and lysed, DNA is captured onto glass-fiber filter. Radioactivity (cpm) as measure for proliferation by counting on a scintillation beta-counter.

FIGS. 10A and 10B show that the selected anti-CD3 1A4, 1C10, 2B4, and 7A3 antibodies had Thymidine incorporation reading on human and cynomolgus PBMC (peripheral blood mononuclear cells). Table 11 shows their KDs by Biacore measurement. In vitro characterization shows anti-CD3 1C10 and 2B4 antibodies are similar to the positive control SP34 anti-CD3 antibody (BD Biosciences)

TABLE-US-00019 TABLE 11 anti-xCD3e ab/bsc_hCD3ed kinetic results for data fitted from 80 nM-0.64 nM Ligand ka kd t.sub.1/2 (min) KD (nM) UCHT1 (+) 1.80E+05 <8.55E-04 >13.5 <4.74 2B4 3.74E+05 2.74E-03 4.21 7.33 1C10 2.96E+05 2.37E-03 4.88 8.00 SP34 (+) 2.84E+05 3.04E-03 3.80 10.73 7A3* 82.70 1A4* 99.97 Note: Data is only reported for satisfactory kinetic fits. (+) = positive controls *Kinetic determinations are rough estimates because antibody is heterogeneous. Only steady state affinity is measured

Example 15: In Vitro Study of the Bispecific Antibody on T Cell Mediated Killing

This example illustrates the in vitro cytotoxicity of the anti-EpCam/CD3 Bispecific in SW480 mixed with healthy donor isolated Pan T cells.

A: Anti-CD antibodies h2B4-1d, TK, hnpsTK, and yaesTK

Human anti-CD3 (h2B4-1d (or h2B4), h2B4-TK (or h2B4-VH-wt VL_TK), h2B4-hnpsTK (or h2B4-VH-hnps VL_TK), and h2B4-yaesTK (or h2B4-VH-yaes VL_TK)) antibodies and human anti-EpCam antibodies were expressed as human IgG2dA engineered with RRRR or EEEE for bispecific exchange as describe in Example 8.

The SW480 was selected as target cell line for cell killing assay and the effector cells and human T cells were purified from human peripheral blood mononuclear cells (huPBMC). Target and effector cells were seeded in 96-well, round bottom plates in cell culture medium containing 5% fetal bovine serum (FBS). The number of target cells was kept constant at 2.times.10.sup.4 cells/well. A 10-fold serial dilution of bispecific antibody, from 3 ug to 3 pg per mL, was added in triplicate to the cells. Total reaction volume was 200 uL. The reactions were incubated for 48 and 72 hours. For the analysis of cytotoxicity, the lactate dehydrogenase (LDH), a stable cytosolic enzyme that was released upon cell lysis, was quantitatively measured by CytoTox 96.RTM. Non-Radioactive Cytotoxicity Assay kit (Promega, G1780). The plate was read on a Vmax kinetic microplate reader (Molecular Devices) at 490 nM. Optical density values were corrected for media background and spontaneous lysis of target and effector cells. Specific cytotoxicity was calculated according to the following formula: [% spec. lysis=490 nM readout of sample-of E+T mixed control)/(490 nM readout of total T lysis-of media control).times.100%] FIGS. 11A and 11B show that all human anti-EpCam_h2B4 bispecific antibodies had cell killing activity on in vitro setting, and antibody mediated T cell activation was monitoring by T cell activation marker. Table 12A shows their EC50. Table 12B shows Biacore KD on the bispecific antibody format.

TABLE-US-00020 TABLE 12A Day2: EC50 (nM) h2B4-1d_Ep 537.1 h2B4-TK_Ep 405.3 h2B4-hnpsTK_Ep 424.7 h2B4-yaesTK_Ep 1126

TABLE-US-00021 TABLE 12B Summary Table for anti-CD3 hlgG2dA bispecifics kinetics at 37.degree. C. Sample ID - bschlgG2dA ka (1/Ms) kd (1/s) t1/2 (min) KD (nM) h2B4-1d_Ep 5.86E+05 2.37E-02 0.49 40.4 h2B4-TK_Ep 6.87E+05 2.13E-02 0.54 31.0 h2B4-hnpsTK_Ep 7.54E+05 2.35E-02 0.49 31.2 h2B4-yaesTK_Ep 4.74E+05 2.58E-02 0.45 54.4

B: Anti-CD Antibodies m25A8, h25A8-B12, and h25A8-B13

Human anti-CD3 h2B4(h2B4_1d) and h25A8 (m25A8, h25A8-B12, and h25A8-B13) and human anti-EpCam antibodies were expressed as human IgG2dA engineered with RRRR or EEEE for bispecific exchange as describe in Example 8.

FIGS. 11C and 11D show that all human anti-EpCam_anti-CD3 bispecific antibodies had cell killing activity on in vitro setting, and antibody mediated T cell activation was monitoring by T cell activation marker. Table 12C shows the EC50 of in vitro cell killing. Table 12D shows the Biacore kinetics on the bispecific antibody format at 37.degree. C. Table 12E shows in vitro characterization using SEC-MALS (Size Exclusion Chromatography with Multi-Angle Light Scattering) and DSC (Differential Scanning Calorimety).

TABLE-US-00022 TABLE 12C EC50 of in vitro cell killing Day 1: EC50 (nM) h2B4-1d_Ep 52.9 m25A8_Ep 127.6 h25A8-B12_Ep 99.36 h25A8-B13_Ep 57.11

TABLE-US-00023 TABLE 12D Summary Table for anti-CD3 hlgG2dA bispecifics kinetics at 37.degree. C. SampleID -bschlgG2dA ka (1/Ms) kd (1/s) t1/2 (min) KD (nM) h25A8-B5_Ep 1.29E+06 5.81E-02 0.20 45.0 h25A8-B8_Ep 1.19E+06 2.22E-02 0.52 18.7 h25A8-B12_Ep 1.15E+06 2.41E-02 0.48 21.0 h25A8-B13_Ep 1.20E+06 2.19E-02 0.53 18.3 h25A8-C8_Ep 1.20E+06 3.01E-02 0.38 25.1 h2B4-1d_Ep 5.86E+05 2.37E-02 0.49 40.4

TABLE-US-00024 TABLE 12E in vitro characterization DSC SEC-MALS Tm1 Tm2 Tm3 % % C. C. C. Monomer Aggregate (CH2) (Fab) (CH3) m28A8 99.9 0.1 66.3 67.8 76.1 hlgG2dA_h25A8-B12 99.2 0.8 70.91 73.06 78.31 hlgG2dA_h25A8-B13 99.5 0.5 70.88 72.86 78.2 hlgG2dA-h2B4TK 98.8 1.4 70.2 74.5 79.4

Example 16: In Vitro Study of the Bispecific Antibody on T Cell Mediated Killing of Primary Myeloma Patient Samples

This example illustrates the in vitro cytotoxicity of the anti-BCMA/CD3 Bispecific in primary myeloma cells.

Human anti-BCMA (P5A2, A02_Rd4_0.6 nM_C01, A02_Rd4_6 nM_C16, Combo_Rd4_0.6 nM_C29, and P6E01 L3PY/H3TAQ) and human anti-CD3 (h2B4) antibodies were expressed as human IgG2dA engineered with EEEE or RRRR for bispecific exchange as describe in Example 8.

Total bone marrow mononuclear cells from myeloma patients were seeded in clear U-bottom plates at total bone marrow mononuclear cell numbers that resulted in 3000-5000 myeloma cells/well. Cells were treated with 10-fold serially diluted bispecific antibody. Five days after treatment, total viable cells were determined by flow cytometry using antibodies to CD138 and CD38 (Biolegend, CA). Cells were incubated with antibodies at 4.degree. in PBS+0.5% FBS for 30 minutes. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 minutes at 4.degree.. Prior to cell acquisition on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. Percent live cells were determined as live cell count in treated vs untreated wells using counting beads. EC50 was calculated by Prism software.

Table 13A shows that all human anti-BCMA_h2B4 bispecific antibodies have cell killing activity on myeloma patient samples and patient T cells are functional effector cells. Table 13B shows killing of one anti-BCMA bispecific on multiple myeloma patient samples with different effector to target (E:T) ratio.

TABLE-US-00025 TABLE 13A Anti-BCMA bispecific (Patient MM00146) EC50 (nM) P6E01 L3PY/H3TAQ 0.015 P5A2 0.946 A02_Rd4_0.6 nM_C01 0.064 A02_Rd4_6 nM_C16 0.029 NNC_2b41d hlgG2dA 3.302

TABLE-US-00026 TABLE 13B Combo_Rd4_0.6 nM_C29 Patient EC50 (nM) E:T MM00146 0.035 1:1 MM00147 0.031 2:1 MM00151 0.02 3:1 MM00152 0.289 1:2

Example 17: ELISPOT of Antibody Secreting Cells from Cynomolgus Monkeys Administered with Anti-BCMA/CD3 Bispecific Antibodies

This example illustrates the depletion of IgG secreting cells in cynomolgus monkey with anti-BCMA/CD3 bispecific antibodies.

Cynomolgus monkeys (n=2) were dosed via intravenous bolus injection with bispecific anti-BCMA_CD3 antibodies (h2B4-VH-hnps VL_TK), A02_Rd4_0.6 nM_C01/H2B4 and Combo_Rd4_0.6 nM_C29/H2B at two doses, day 1 and day 8, of 100 ug/kg and 300 ug/kg. Animals were observed twice daily and at each blood collection time point. Peripheral blood mononuclear cells (PBMC) were sampled on days -6, 4 and 10. Bone marrow samples were taken on day 10 when animals were necropsied.

Blood was collected into Becton Dickinson.RTM. CPT.TM. Cell Preparation Tubes containing sodium heparin and a density gradient, and then PBMCs were collected at the gradient interface following centrifugation.

A sample of bone marrow (from femur) was collected by flushing with approximately 5 mL of 100% fetal bovine serum (FBS) and then single cell suspensions were prepared by suspending flushed marrow in 50 ml of buffer.

Cells were counted using the Cellometer Vision and adjusted with complete RPMI 1640 culture medium to a concentration of 5.times.10.sup.6 cells per mL for PBMC and 2.times.10.sup.6 cells per mL for bone marrow cells. Total IgG-secreting cells were enumerated using the ELISpot.sup.BASIC kit from Mabtech (#3850-2HW-Plus). Briefly, PBMC or bone marrow cells were added to triplicate wells at specified concentrations (PBMCs at 5.times.10.sup.5/well, and bone marrow cells at 2.times.10.sup.5/well), and then cells were serially diluted in the plate. After an overnight incubation, plates were washed and a biotinylated detection antibody was added. Plates were incubated for 2 hours and streptavidin-HRP was added for 1 hour. IgG spots were visualized using TMB substrate solution and counted using the ImmunoSpot Imaging Analyzer system (CTL) and ImmunoSpot 5.1 software. Data were expressed as the mean (+/-SD) number of IgG-secreting cells from triplicate samples.

The resulting IgG-secreting cell count in PBMC and in bone marrow are listed in Tables 14A and 14B, respectively. Depletion of IgG-secreting cells was seen for both anti-BCMA/CD3 bispecific antibodies in PBMC as compared to pre-dose and bone marrow as compared to vehicle and negative control. A dose dependent effect was seen in the bone marrow.

TABLE-US-00027 TABLE 14A Day PBMC -6 4 10 Vehicle 204, 320 323, 538 127, 137 0.1 mg/kg Combo_Rd4_0.6 107, 128 5, 0 0, 0 nM_C29 0.3 mg/kg Combo_Rd4_0.6 304, 362 0, 5 0, 0 nM_C29 0.1 mg/kg A02_Rd4_0.6 447, 672 16, 27 21, 10 nM_C01 0.3 mg/kg A02_Rd4_0.6 512, 224 25, 8 0, 0 nM_C01 0.3 mg/kg NNC_2b41d 139, 361 1345, 1154 992, 928

TABLE-US-00028 TABLE 14B Bone Marrow Day 10 Vehicle 2614, 8093 0.1 mg/kg Combo_Rd4_0.6 nM_C29 35, 18 0.3 mg/kg Combo_Rd4_0.6 nM_C29 35, 22 0.1 mg/kg A02_Rd4_0.6 nM_C01 996, 960 0.3 mg/kg A02_Rd4_0.6 nM_C01 2170, 93 0.3 mg/kg NNC_2b41d 5980, 2893

Example 18: Anti-BCMA/CD3 Bispecific Induce Tumor Regression and Inhibition in MM1.S Tumor Model

This example illustrates tumor regression and inhibition in an orthotopic MM1.S myeloma model.

In vivo efficacy study of BCMA bispecifics was performed with MM1.S, expressing luciferase and GFP, orthotopic model. One day prior to tumor cell injection, mice were irradiated with 100cGy using RS 2000 Biological Research Irradiator (RAD Source Technologies, GA). Five million MM1.S LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female Nod/Scid/IL2Rg.sup.-/- (NSG) animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enabled monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 15E6 for all animals, the animals were injected through bolus tail vein with 20 million expanded T cells from PBMC. Briefly, pan-T cells purchased from AllCells (Alameda, Calif.) were activated with human T Cell Activation/Expansion Kit (Miltenyi, San Diego, Calif.). After three days, 15U/mL of IL2 (ebioscience, San Diego, Calif.) was added every two days until day 11. Cells were harvested, activation/expansion beads were magnetically removed, and cells were washed and resuspended in PBS. One day post T cell injection, mice were imaged as described above and animals were randomized into groups of seven mice; A02_Rd4_0.6 nM_C01 at 0.03 mg/kg and 0.3 mg/kg and Combo_Rd4_0.6 nM_C29 at 0.03 mg/kg, 0.1 mg/kg and 0.3 mg/kg. A single dose of human anti-BCMA/CD3 (h2B4-VH-wt VL_TK) bispecific and negative (NNC) control bispecific antibody was administered through bolus tail vein injection. Animals were sacrificed when they exhibited hindlimb paralysis, an endpoint for MM1.S orthotopic model. FIG. 12 shows that a single dose of human anti-BCMA/CD3 bispecific antibody resulted in tumor regression in a dose-dependent manner.

Example 19: Two Doses of Anti-BCMA/CD3 Bispecific Induce Tumor Regression in Aggressive Molp8 Tumor Model

This example illustrates tumor regression with two doses of anti-BCMA/CD3 bispecific antibodies in an orthotopic Molp8 myeloma model.

In vivo efficacy study of BCMA bispecifics was performed with Molp8, expressing luciferase and GFP, orthotopic model. Two million Molp8 LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female NSG animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enabled monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). When the total flux reached an average of 25E6 for all animals were randomized into three groups of seven mice; 1) Combo_Rd4_0.6 nM_C29, 0.3 mg/kg, 2) Combo_Rd4_0.6 nM_C29, 0.3 mg/kg, two doses and 3) NNC_2B4, 0.3 mg/kg, two doses. The animals were injected through bolus tail vein with 20 million expanded T cells as described in Example 18. Two days post T cell injection, mice were dosed with bispecific antibodies. Animals were sacrificed when they exhibited weight loss of more than 15%, an endpoint for Molp8 orthotopic model. FIG. 13 shows that two doses of human anti-BCMA/CD3 (h2B4-VH-wt VL_TK) bispecific antibody resulted in increased tumor regression.

Example 20: Anti-BCMA/CD3 Bispecific in Combination with Standard of Care for Multiple Myeloma in Orthotopic Molp8 Tumor Model

This example demonstrates no opposing effects on anti-BCMA/CD3 bispecific antibodies when combined with bortezomib or lenalidomide and better potency with anti-BCMA/CD3 bispecific antibodies as compared to bortezomib and lenalidomie combined.

In vivo efficacy study of BCMA bispecifics was performed with Molp8, expressing luciferase and GFP, orthotopic model. Two million Molp8 LucGFP cells were injected intravenously through the tail vein into 6-8 weeks old female NSG animals. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, Ill.) (200 uL per animal at 15 mg/mL), followed by anesthesia with isofluorane and subsequent whole body bioluminescence imaging (BLI) enabled monitoring of tumor burden. Bioluminescent signals emitted by the interaction between luciferase expressed by the tumor cells and luciferin were captured by imaging using an IVIS Spectrum CT (Perkin Elmer, Mass.) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, Calif.). The animals were injected through bolus tail vein on day 7 with 20 million expanded T cells as described in Example 18. Two days post T cell injection, mice were imaged and randomized into five groups of seven mice with an average of 17E6 total flux/group: 1) Combo_Rd4_0.6 nM_C29, 0.3 mg/kg, 2) Combo_Rd4_0.6 nM_C29, 0.3 mg/kg and 1 mg/kg bortezomib, 3) Combo_Rd4_0.6 nM_C29, 0.3 mg/kg and 50 mg/kg lenalidomide, 4) 1 mg/kg bortezomib and 50 mg/kg lenalidomide and 5) vehicle. Anti-BCMA/CD3 (in PBS) was injected through bolus tail vein injection, bortezomib (in PBS) was administrated via intraperitoneal injection and lenalidomide (30% PEG400/5% propylene glycol/0.5% Tween80) via oral gavage. Vehicle consisted of 30% PEG400/5% propylene glycol/0.5% Tween80, which was administrated via oral gavage. Animals were sacrificed when they exhibit weight loss of more than 15%, an endpoint for Molp8 orthotopic model. FIG. 14 shows that combining an anti-BCMA/CD3 (h2B4-VH-hnps VL-TK) bispecific antibody with bortezomib or lenalidomide did not have a negative effect on the efficacy of the anti-BCMA/CD3 bispecific antibody. In this model, anti-BCMA/CD3 bispecific antibody alone or in combination with lenalidomide or bortezomib is more efficacious than lenalidomide and bortezomib combined.

Example 21: In Vitro Study of Anti-BCMA/CD3 Bispecific in Combination with Lenalidomide, Carfilzomib or Doxorubicin on OPM2 Cell Line

This example illustrates no adverse effects on T cell function when combined with carfilzomib, doxorubicin, and lenalidomide for anti-BCMA/CD3 bispecific antibody activity as compared to the bispecific antibody alone.

CD3+ T cells from PBMC were negatively selected using Pan T Cell Isolation kit, human (Miltenyi, San Diego Calif.). OPM2 cells and CD3+ T-cells were seeded in clear U-bottom plates 20000 and 100000 cells/well, respectively. OPM2 and CD3+ T cells were first incubated with the standard of care for two hours at 37.degree.. 1.56 nM carfilzomib and 6.25 nM doxorubicin were diluted in PBS containing 0.02% DMSO. Lenalidomide was diluted in PBS containing 0.1% DMSO at 195 nM. Cells were treated with 10-fold serially diluted bispecific antibody. Three days after treatment, total viable cells were determined by flow cytometry using antibodies to CD138, CD4, and CD8 (Biolegend). Cells were incubated with antibodies at 4.degree. in PBS+0.5% FBS for 30 minutes. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 minutes at 4.degree.. Prior to cell acquisition on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. Percent live cells were determined as live cell count in treated vs untreated wells using counting beads. FIGS. 15A, 15B, and 15C, respectively, show that carfilzomib, lenalidomide, and doxorubicin do not have a negative effect on the function of Combo_Rd4_0.6 nM_C29-CD3 (h2B4-VH-hnps VL-TK) bispecific antibody on OPM2 cells.

Example 22: In Vitro Study of Anti-BCMA/CD3 Bispecific in Combination with Lenalidomide and Carfilzomib on KMS12BM Cell Line

This example illustrates synergistic effects on anti-BCMA/CD3 bispecific function when combined with carfilzomib and lenalidomide as compared to each molecule alone.

CD3+ T cells from PBMC were negatively selected using Pan T Cell Isolation kit, human (Miltenyi, San Diego Calif.). KMS12BM cells and CD3+ T-cells were seeded in clear U-bottom plates 20000 and 100000 cells/well, respectively. Cells were treated with 0.017 nM anti-BCMA/CD3 bispecific in combination with carfilzomib and a range of concentration for lenalidomide. 1.25 nM carfilzomib was diluted in PBS containing 0.02% DMSO. Lenalidomide was diluted in PBS containing 0.1% DMSO starting at 4 uM diluted 4-fold. Three days after treatment, total viable cells were determined by flow cytometry using antibodies to CD138, CD4, and CD8 (Biolegend, CA). Cells were incubated with antibodies at 4.degree. in PBS+0.5% FBS for 30 minutes. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 minutes at 4.degree.. Prior to cell acquisition on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. Percent live cells were determined as live cell count in treated versus untreated wells using counting beads. FIG. 16 shows that at the concentrations tested, carfilzomib, lenalidomide, and anti-BCMA/CD3 (h2B4-VH-hnps VL-TK) bispecific antibody had very little single agent cytotoxic function. When all three agents were combined, a synergistic effect was observed at a dose-dependent lenalidomide concentration in KMS12BM cells.

Although the disclosed teachings have been described with reference to various applications, methods, kits, and compositions, it will be appreciated that various changes and modifications can be made without departing from the teachings herein and the claimed invention below. The foregoing examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented herein. While the present teachings have been described in terms of these exemplary embodiments, the skilled artisan will readily understand that numerous variations and modifications of these exemplary embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the current teachings.

All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

The foregoing description and Examples detail certain specific embodiments of the invention and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof.

SEQUENCE LISTINGS

1

5021109PRTArtificial SequenceSynthetic Construct 1Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 2119PRTArtificial SequenceSynthetic Construct 2Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 3119PRTArtificial SequenceSynthetic Construct 3Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ala Gln Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 4109PRTArtificial SequenceSynthetic Construct 4Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 5109PRTArtificial SequenceSynthetic Construct 5Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 6109PRTArtificial SequenceSynthetic Construct 6Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 7121PRTArtificial SequenceSynthetic Construct 7Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Arg Val Ser Pro Ile Ala Ala Leu Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 8119PRTArtificial SequenceSynthetic Construct 8Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ala Pro Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 9109PRTArtificial SequenceSynthetic Construct 9Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 10109PRTArtificial SequenceSynthetic Construct 10Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 11109PRTArtificial SequenceSynthetic Construct 11Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 12109PRTArtificial SequenceSynthetic Construct 12Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 13109PRTArtificial SequenceSynthetic Construct 13Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 14109PRTArtificial SequenceSynthetic Construct 14Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 15109PRTArtificial SequenceSynthetic Construct 15Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 16109PRTArtificial SequenceSynthetic Construct 16Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 17109PRTArtificial SequenceSynthetic Construct 17Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 18109PRTArtificial SequenceSynthetic Construct 18Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Pro Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 19109PRTArtificial SequenceSynthetic Construct 19Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala His 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 20109PRTArtificial SequenceSynthetic Construct 20Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Phe 20 25 30 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile

Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 21109PRTArtificial SequenceSynthetic Construct 21Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro His 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 22109PRTArtificial SequenceSynthetic Construct 22Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys Tyr Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 23109PRTArtificial SequenceSynthetic Construct 23Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys Phe Tyr Pro Tyr Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 24119PRTArtificial SequenceSynthetic Construct 24Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Arg 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 25119PRTArtificial SequenceSynthetic Construct 25Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asp Tyr Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 26119PRTArtificial SequenceSynthetic Construct 26Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Gln Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 27119PRTArtificial SequenceSynthetic Construct 27Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Leu Thr Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 28119PRTArtificial SequenceSynthetic Construct 28Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser His Ala Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 29119PRTArtificial SequenceSynthetic Construct 29Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Leu 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 30119PRTArtificial SequenceSynthetic Construct 30Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Tyr Ala Gly Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 31119PRTArtificial SequenceSynthetic Construct 31Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Ala Ala Glu Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 32119PRTArtificial SequenceSynthetic Construct 32Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Val Ser Pro Ile Ala Ala Gln Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 33115PRTArtificial SequenceSynthetic Construct 33Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 34108PRTArtificial SequenceSynthetic Construct 34Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 35115PRTArtificial SequenceSynthetic Construct 35Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Ala Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 36108PRTArtificial SequenceSynthetic Construct 36Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 37115PRTArtificial SequenceSynthetic Construct 37Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Met Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 38108PRTArtificial SequenceSynthetic Construct 38Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 39115PRTArtificial SequenceSynthetic Construct 39Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35

40 45 Ser Ala Ile Ser Asp Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 40108PRTArtificial SequenceSynthetic Construct 40Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asp Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Thr Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 41108PRTArtificial SequenceSynthetic Construct 41Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 42115PRTArtificial SequenceSynthetic Construct 42Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Thr Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 43108PRTArtificial SequenceSynthetic Construct 43Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Tyr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 44115PRTArtificial SequenceSynthetic Construct 44Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 45108PRTArtificial SequenceSynthetic Construct 45Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 46115PRTArtificial SequenceSynthetic Construct 46Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 47108PRTArtificial SequenceSynthetic Construct 47Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Leu Asp Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 48115PRTArtificial SequenceSynthetic Construct 48Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 49108PRTArtificial SequenceSynthetic Construct 49Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 50115PRTArtificial SequenceSynthetic Construct 50Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Asp Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 51108PRTArtificial SequenceSynthetic Construct 51Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Leu Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 52115PRTArtificial SequenceSynthetic Construct 52Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Lys Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 53108PRTArtificial SequenceSynthetic Construct 53Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Thr Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 54115PRTArtificial SequenceSynthetic Construct 54Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 55108PRTArtificial SequenceSynthetic Construct 55Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Tyr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 56115PRTArtificial SequenceSynthetic Construct 56Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Gly Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 57108PRTArtificial SequenceSynthetic Construct 57Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Glu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 58115PRTArtificial SequenceSynthetic Construct 58Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 59108PRTArtificial SequenceSynthetic Construct 59Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Glu Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Gly Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 60115PRTArtificial SequenceSynthetic Construct 60Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Cys Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 61108PRTArtificial SequenceSynthetic Construct 61Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Glu Met Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala His Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 62115PRTArtificial SequenceSynthetic Construct 62Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 63108PRTArtificial SequenceSynthetic Construct 63Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 64115PRTArtificial SequenceSynthetic Construct 64Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Trp Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 65108PRTArtificial SequenceSynthetic Construct 65Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Gln 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 66115PRTArtificial SequenceSynthetic Construct 66Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Met Ser Ser Gly Gly Pro Leu Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ala Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 67108PRTArtificial SequenceSynthetic Construct 67Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 68115PRTArtificial SequenceSynthetic Construct 68Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Met Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 69108PRTArtificial SequenceSynthetic Construct 69Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gly Pro Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 70115PRTArtificial SequenceSynthetic Construct 70Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Tyr Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 71108PRTArtificial SequenceSynthetic Construct 71Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Trp Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 72115PRTArtificial SequenceSynthetic Construct 72Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 73108PRTArtificial SequenceSynthetic Construct 73Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 74115PRTArtificial SequenceSynthetic Construct 74Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 75108PRTArtificial SequenceSynthetic Construct 75Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Phe Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 76115PRTArtificial SequenceSynthetic Construct 76Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 77108PRTArtificial SequenceSynthetic Construct 77Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Thr Ser Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 78115PRTArtificial SequenceSynthetic Construct 78Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 79108PRTArtificial SequenceSynthetic Construct 79Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Glu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Val Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 80109PRTArtificial SequenceSynthetic Construct 80Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Tyr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro 85 90 95 Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 81108PRTArtificial SequenceSynthetic Construct 81Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 82108PRTArtificial SequenceSynthetic Construct 82Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 83115PRTArtificial SequenceSynthetic Construct 83Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Trp Ser Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 84108PRTArtificial SequenceSynthetic Construct 84Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Trp Leu Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Glu Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 85108PRTArtificial SequenceSynthetic Construct 85Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 86108PRTArtificial SequenceSynthetic Construct 86Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Leu 20 25 30 Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 87115PRTArtificial SequenceSynthetic Construct 87Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Thr Val Gly Ser Gly Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 88108PRTArtificial SequenceSynthetic Construct 88Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ala Cys Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 89108PRTArtificial SequenceSynthetic Construct 89Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Cys Asp Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Arg Ser Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 90108PRTArtificial SequenceSynthetic Construct 90Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ala Val Pro Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 91108PRTArtificial SequenceSynthetic Construct 91Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Cys Ser Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 92115PRTArtificial SequenceSynthetic Construct 92Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 93108PRTArtificial SequenceSynthetic Construct 93Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Arg Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Lys Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 94108PRTArtificial SequenceSynthetic Construct 94Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Ala 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Cys Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 95115PRTArtificial SequenceSynthetic Construct 95Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Ile His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 96108PRTArtificial SequenceSynthetic Construct 96Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Trp Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Cys Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 97115PRTArtificial SequenceSynthetic Construct 97Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala His Ile Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 98108PRTArtificial SequenceSynthetic Construct 98Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 99115PRTArtificial SequenceSynthetic Construct 99Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 100108PRTArtificial SequenceSynthetic Construct 100Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Pro 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 101115PRTArtificial SequenceSynthetic Construct 101Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 102108PRTArtificial SequenceSynthetic Construct 102Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 103108PRTArtificial SequenceSynthetic Construct 103Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Glu Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 104115PRTArtificial SequenceSynthetic Construct 104Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 105108PRTArtificial SequenceSynthetic Construct 105Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Gln 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 106115PRTArtificial SequenceSynthetic Construct 106Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Thr Trp Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 107108PRTArtificial SequenceSynthetic Construct 107Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Lys Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 108108PRTArtificial SequenceSynthetic Construct 108Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Val 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 109108PRTArtificial SequenceSynthetic Construct 109Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ile Ala Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Val Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110115PRTArtificial SequenceSynthetic Construct 110Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Leu Phe Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 111108PRTArtificial SequenceSynthetic Construct 111Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Pro Arg Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Asp Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 112115PRTArtificial SequenceSynthetic Construct 112Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 113108PRTArtificial SequenceSynthetic Construct 113Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Glu Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 114114PRTArtificial SequenceSynthetic Construct 114Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser 115108PRTArtificial SequenceSynthetic Construct 115Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 116108PRTArtificial SequenceSynthetic Construct 116Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Met 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 117108PRTArtificial SequenceSynthetic Construct 117Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu 20 25

30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Gly Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 118115PRTArtificial SequenceSynthetic Construct 118Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ala Asp Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 119108PRTArtificial SequenceSynthetic Construct 119Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Pro Ile Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 120115PRTArtificial SequenceSynthetic Construct 120Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Asp Ser Gly Gly Phe Val Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 121108PRTArtificial SequenceSynthetic Construct 121Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Phe Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 122115PRTArtificial SequenceSynthetic Construct 122Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 123108PRTArtificial SequenceSynthetic Construct 123Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 124108PRTArtificial SequenceSynthetic Construct 124Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Tyr Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 125115PRTArtificial SequenceSynthetic Construct 125Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Cys Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 126108PRTArtificial SequenceSynthetic Construct 126Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 127115PRTArtificial SequenceSynthetic Construct 127Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 128108PRTArtificial SequenceSynthetic Construct 128Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 1295PRTArtificial SequenceSynthetic Construct 129Ser Tyr Ala Met Thr 1 5 1307PRTArtificial SequenceSynthetic Construct 130Gly Phe Thr Phe Gly Ser Tyr 1 5 13110PRTArtificial SequenceSynthetic Construct 131Gly Phe Thr Phe Gly Ser Tyr Ala Met Thr 1 5 10 13217PRTArtificial SequenceSynthetic Construct 132Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1336PRTArtificial SequenceSynthetic Construct 133Ser Gly Ser Gly Gly Asn 1 5 13410PRTArtificial SequenceSynthetic Construct 134Val Ser Pro Ile Ala Ser Gly Met Asp Tyr 1 5 10 13510PRTArtificial SequenceSynthetic Construct 135Val Ser Pro Ile Ala Ala Gln Met Asp Tyr 1 5 10 13610PRTArtificial SequenceSynthetic Construct 136Val Ser Pro Ile Ala Ala Leu Met Asp Tyr 1 5 10 13710PRTArtificial SequenceSynthetic Construct 137Val Ser Pro Ile Ala Ala Pro Met Asp Tyr 1 5 10 13817PRTArtificial SequenceSynthetic Construct 138Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Arg Lys 1 5 10 15 Gly 13917PRTArtificial SequenceSynthetic Construct 139Ala Ile Asp Tyr Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1406PRTArtificial SequenceSynthetic Construct 140Asp Tyr Ser Gly Gly Asn 1 5 14117PRTArtificial SequenceSynthetic Construct 141Ala Ile Ser Tyr Gln Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1426PRTArtificial SequenceSynthetic Construct 142Ser Tyr Gln Gly Gly Asn 1 5 14317PRTArtificial SequenceSynthetic Construct 143Ala Ile Ser Leu Thr Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1446PRTArtificial SequenceSynthetic Construct 144Ser Leu Thr Gly Gly Asn 1 5 14517PRTArtificial SequenceSynthetic Construct 145Ala Ile Ser His Ala Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1466PRTArtificial SequenceSynthetic Construct 146Ser His Ala Gly Gly Asn 1 5 14717PRTArtificial SequenceSynthetic Construct 147Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Leu Lys 1 5 10 15 Gly 14810PRTArtificial SequenceSynthetic Construct 148Val Ser Pro Ile Tyr Ala Gly Met Asp Tyr 1 5 10 14910PRTArtificial SequenceSynthetic Construct 149Val Ser Pro Ile Ala Ala Glu Met Asp Tyr 1 5 10 1505PRTArtificial SequenceSynthetic Construct 150Ser Tyr Ala Met Asn 1 5 1517PRTArtificial SequenceSynthetic Construct 151Gly Phe Thr Phe Ser Ser Tyr 1 5 15210PRTArtificial SequenceSynthetic Construct 152Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 1 5 10 15317PRTArtificial SequenceSynthetic Construct 153Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1546PRTArtificial SequenceSynthetic Construct 154Ser Asp Ser Gly Gly Ser 1 5 1556PRTArtificial SequenceSynthetic Construct 155Tyr Trp Pro Met Asp Ile 1 5 1565PRTArtificial SequenceSynthetic Construct 156Ser Tyr Pro Met Ser 1 5 15710PRTArtificial SequenceSynthetic Construct 157Gly Phe Thr Phe Ser Ser Tyr Pro Met Ser 1 5 10 15817PRTArtificial SequenceSynthetic Construct 158Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1596PRTArtificial SequenceSynthetic Construct 159Gly Gly Ser Gly Gly Ser 1 5 16017PRTArtificial SequenceSynthetic Construct 160Ala Ile Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1616PRTArtificial SequenceSynthetic Construct 161Tyr Trp Pro Met Asp Ser 1 5 16217PRTArtificial SequenceSynthetic Construct 162Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 16317PRTArtificial SequenceSynthetic Construct 163Ala Ile Ser Asp Ser Gly Gly Ser Ala Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1646PRTArtificial SequenceSynthetic Construct 164Tyr Trp Pro Met Ser Leu 1 5 16517PRTArtificial SequenceSynthetic Construct 165Ala Ile Ser Asp Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1666PRTArtificial SequenceSynthetic Construct 166Ser Asp Phe Gly Gly Ser 1 5 16717PRTArtificial SequenceSynthetic Construct 167Ala Ile Thr Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1686PRTArtificial SequenceSynthetic Construct 168Thr Ala Ser Gly Gly Ser 1 5 16917PRTArtificial SequenceSynthetic Construct 169Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1706PRTArtificial SequenceSynthetic Construct 170Tyr Trp Pro Met Thr Pro 1 5 17117PRTArtificial SequenceSynthetic Construct 171Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1726PRTArtificial SequenceSynthetic Construct 172Leu Asp Ser Gly Gly Ser 1 5 1736PRTArtificial SequenceSynthetic Construct 173Tyr Trp Pro Met Ser Asp 1 5 17417PRTArtificial SequenceSynthetic Construct 174Ala Ile Ser Asp Ser Gly Gly Ser Lys Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 17517PRTArtificial SequenceSynthetic Construct 175Ala Ile Ser Asp Ser Gly Gly Ser Gly Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 17617PRTArtificial SequenceSynthetic Construct 176Ala Ile Ser Asp Ser Gly Gly Ser Cys Trp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 17717PRTArtificial SequenceSynthetic Construct 177Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1786PRTArtificial SequenceSynthetic Construct 178Phe Ala Ser Gly Gly Ser 1 5 1796PRTArtificial SequenceSynthetic Construct 179Ser Gly Trp Gly Gly Ser 1 5 18017PRTArtificial SequenceSynthetic Construct 180Ala Ile Met Ser Ser Gly Gly Pro Leu Tyr Tyr Ala Asp Ser Val Lys 1

5 10 15 Gly 1816PRTArtificial SequenceSynthetic Construct 181Met Ser Ser Gly Gly Pro 1 5 1826PRTArtificial SequenceSynthetic Construct 182Tyr Trp Pro Met Ala Leu 1 5 18317PRTArtificial SequenceSynthetic Construct 183Ala Ile Leu Met Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1846PRTArtificial SequenceSynthetic Construct 184Leu Met Ser Gly Gly Ser 1 5 18517PRTArtificial SequenceSynthetic Construct 185Ala Ile Ser Asp Ser Gly Gly Tyr Arg Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1866PRTArtificial SequenceSynthetic Construct 186Ser Asp Ser Gly Gly Tyr 1 5 18717PRTArtificial SequenceSynthetic Construct 187Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1886PRTArtificial SequenceSynthetic Construct 188Leu Ser Ser Gly Gly Ser 1 5 1896PRTArtificial SequenceSynthetic Construct 189Tyr Trp Pro Met Ser Pro 1 5 19017PRTArtificial SequenceSynthetic Construct 190Ala Ile Gly Gly Ser Gly Gly Trp Ser Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1916PRTArtificial SequenceSynthetic Construct 191Gly Gly Ser Gly Gly Trp 1 5 19217PRTArtificial SequenceSynthetic Construct 192Ala Thr Val Gly Ser Gly Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1936PRTArtificial SequenceSynthetic Construct 193Val Gly Ser Gly Gly Ser 1 5 19417PRTArtificial SequenceSynthetic Construct 194Ala Ile Gly Gly Ser Gly Gly Ser Ile His Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 19517PRTArtificial SequenceSynthetic Construct 195Ala His Ile Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 1966PRTArtificial SequenceSynthetic Construct 196Ile Gly Ser Gly Gly Ser 1 5 1976PRTArtificial SequenceSynthetic Construct 197Tyr Trp Pro Met Asp Pro 1 5 19817PRTArtificial SequenceSynthetic Construct 198Ala Ile Gly Gly Ser Gly Gly Ser Leu Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 19917PRTArtificial SequenceSynthetic Construct 199Ala Ile Gly Gly Ser Gly Thr Trp Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 2006PRTArtificial SequenceSynthetic Construct 200Gly Gly Ser Gly Thr Trp 1 5 20117PRTArtificial SequenceSynthetic Construct 201Ala Leu Phe Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 2026PRTArtificial SequenceSynthetic Construct 202Phe Gly Ser Gly Gly Ser 1 5 20317PRTArtificial SequenceSynthetic Construct 203Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 2046PRTArtificial SequenceSynthetic Construct 204Leu Gly Ser Gly Gly Ser 1 5 2056PRTArtificial SequenceSynthetic Construct 205Tyr Trp Pro Met Ala Asp 1 5 20617PRTArtificial SequenceSynthetic Construct 206Ala Ile Ser Asp Ser Gly Gly Phe Val Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 2076PRTArtificial SequenceSynthetic Construct 207Ser Asp Ser Gly Gly Phe 1 5 20817PRTArtificial SequenceSynthetic Construct 208Ala Cys Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 20912PRTArtificial SequenceSynthetic Construct 209Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 2107PRTArtificial SequenceSynthetic Construct 210Gly Ala Ser Ser Arg Ala Thr 1 5 21110PRTArtificial SequenceSynthetic Construct 211Gln His Tyr Gly Ser Pro Pro Ser Phe Thr 1 5 10 21212PRTArtificial SequenceSynthetic Construct 212Arg Ala Ser Gln Ser Leu Gly Ser Phe Tyr Leu Ala 1 5 10 21310PRTArtificial SequenceSynthetic Construct 213Lys His Tyr Gly Trp Pro Pro Ser Phe Thr 1 5 10 21410PRTArtificial SequenceSynthetic Construct 214Gln His Tyr Asn Tyr Pro Pro Ser Phe Thr 1 5 10 21512PRTArtificial SequenceSynthetic Construct 215Arg Ala Ser Gln Ser Val Gly Asp Phe Tyr Leu Ala 1 5 10 21610PRTArtificial SequenceSynthetic Construct 216Gln His Tyr Pro Tyr Pro Pro Ser Phe Thr 1 5 10 21712PRTArtificial SequenceSynthetic Construct 217Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Pro Ser 1 5 10 21812PRTArtificial SequenceSynthetic Construct 218Arg Ala Ser Gln Ser Val Ser Ala His Tyr Leu Ala 1 5 10 21912PRTArtificial SequenceSynthetic Construct 219Arg Ala Ser Gln Ser Val Ser Ser Phe Phe Leu Ala 1 5 10 22010PRTArtificial SequenceSynthetic Construct 220Lys Tyr Tyr Pro Tyr Pro Pro Ser Phe Thr 1 5 10 2217PRTArtificial SequenceSynthetic Construct 221Asp Ala Ser Ile Arg Ala Thr 1 5 2229PRTArtificial SequenceSynthetic Construct 222Gln Gln Tyr Gly Ser Trp Pro Leu Thr 1 5 22312PRTArtificial SequenceSynthetic Construct 223Arg Ala Ser Gln Ser Val Ser Val Leu Tyr Leu Ala 1 5 10 2249PRTArtificial SequenceSynthetic Construct 224Gln Gln Tyr Gln Arg Trp Pro Leu Thr 1 5 2259PRTArtificial SequenceSynthetic Construct 225Gln Gln Tyr Gln Ser Trp Pro Leu Thr 1 5 22612PRTArtificial SequenceSynthetic Construct 226Arg Ala Ser Gln Ser Val Ser Asp Leu Tyr Leu Ala 1 5 10 2279PRTArtificial SequenceSynthetic Construct 227Gln Gln Tyr Gln Thr Trp Pro Leu Thr 1 5 22812PRTArtificial SequenceSynthetic Construct 228Arg Ala Ser Gln Ser Val Ser Asn Leu Tyr Leu Ala 1 5 10 2299PRTArtificial SequenceSynthetic Construct 229Gln Gln Tyr Gln Gly Trp Pro Leu Thr 1 5 23012PRTArtificial SequenceSynthetic Construct 230Arg Ala Ser Gln Ser Val Ser Ala Tyr Tyr Leu Ala 1 5 10 2319PRTArtificial SequenceSynthetic Construct 231Gln Gln Tyr Glu Arg Trp Pro Leu Thr 1 5 23212PRTArtificial SequenceSynthetic Construct 232Arg Ala Ser Gln Ser Val Ser Ser Leu Tyr Leu Ala 1 5 10 2339PRTArtificial SequenceSynthetic Construct 233Gln Gln Tyr Gln Val Trp Pro Leu Thr 1 5 2349PRTArtificial SequenceSynthetic Construct 234Gln Gln Tyr Leu Asp Trp Pro Leu Thr 1 5 23512PRTArtificial SequenceSynthetic Construct 235Arg Ala Ser Gln Ser Val Ser Ala Leu Tyr Leu Ala 1 5 10 2369PRTArtificial SequenceSynthetic Construct 236Gln Gln Tyr Leu Ala Trp Pro Leu Thr 1 5 2379PRTArtificial SequenceSynthetic Construct 237Gln Gln Tyr Phe Thr Trp Pro Leu Thr 1 5 23812PRTArtificial SequenceSynthetic Construct 238Arg Ala Ser Gln Ser Val Ser Pro Tyr Tyr Leu Ala 1 5 10 23912PRTArtificial SequenceSynthetic Construct 239Arg Ala Ser Gln Ser Val Ser Val Glu Tyr Leu Ala 1 5 10 2409PRTArtificial SequenceSynthetic Construct 240Gln Gln Tyr Ala Arg Trp Pro Leu Thr 1 5 24112PRTArtificial SequenceSynthetic Construct 241Arg Ala Ser Gln Ser Val Ser Glu Leu Tyr Leu Ala 1 5 10 2429PRTArtificial SequenceSynthetic Construct 242Gln Gln Tyr Phe Gly Trp Pro Leu Thr 1 5 24312PRTArtificial SequenceSynthetic Construct 243Arg Ala Ser Gln Ser Val Glu Met Ser Tyr Leu Ala 1 5 10 2449PRTArtificial SequenceSynthetic Construct 244Gln Gln Tyr Ala His Trp Pro Leu Thr 1 5 24512PRTArtificial SequenceSynthetic Construct 245Arg Ala Ser Gln Ser Val Ser Ala Gln Tyr Leu Ala 1 5 10 24612PRTArtificial SequenceSynthetic Construct 246Gly Pro Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 24712PRTArtificial SequenceSynthetic Construct 247Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Trp Ala 1 5 10 2489PRTArtificial SequenceSynthetic Construct 248Gln Gln Tyr Glu Ser Trp Pro Leu Thr 1 5 24912PRTArtificial SequenceSynthetic Construct 249Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 25012PRTArtificial SequenceSynthetic Construct 250Arg Ala Ser Gln Ser Val Ser Phe Leu Tyr Leu Ala 1 5 10 25112PRTArtificial SequenceSynthetic Construct 251Arg Ala Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala 1 5 10 2527PRTArtificial SequenceSynthetic Construct 252Asp Ala Ser Ser Arg Ala Pro 1 5 2539PRTArtificial SequenceSynthetic Construct 253Gln Gln Tyr Ser Thr Ser Pro Leu Thr 1 5 25412PRTArtificial SequenceSynthetic Construct 254Arg Ala Ser Gln Ser Val Ser Pro Glu Tyr Leu Ala 1 5 10 2559PRTArtificial SequenceSynthetic Construct 255Gln Gln Tyr Ser Val Trp Pro Leu Thr 1 5 2569PRTArtificial SequenceSynthetic Construct 256Gln Gln Tyr Ser Ala Trp Pro Leu Thr 1 5 25712PRTArtificial SequenceSynthetic Construct 257Arg Ala Ser Gln Ser Val Ser Ser Val Tyr Leu Ala 1 5 10 2589PRTArtificial SequenceSynthetic Construct 258Gln Gln Tyr Ser Thr Trp Pro Leu Thr 1 5 2599PRTArtificial SequenceSynthetic Construct 259Gln Gln Tyr Ser Arg Trp Pro Leu Thr 1 5 26012PRTArtificial SequenceSynthetic Construct 260Arg Ala Ser Gln Ser Val Ser Pro Leu Tyr Leu Ala 1 5 10 2619PRTArtificial SequenceSynthetic Construct 261Gln Gln Tyr Ser Ala Phe Pro Leu Thr 1 5 26212PRTArtificial SequenceSynthetic Construct 262Trp Leu Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala 1 5 10 2639PRTArtificial SequenceSynthetic Construct 263Gln Gln Tyr Ser Glu Trp Pro Leu Thr 1 5 2649PRTArtificial SequenceSynthetic Construct 264Gln Gln Tyr Ser Ser Trp Pro Leu Thr 1 5 26512PRTArtificial SequenceSynthetic Construct 265Arg Ala Ser Gln Ser Val Ser Ser Leu Phe Leu Ala 1 5 10 26612PRTArtificial SequenceSynthetic Construct 266Ala Cys Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala 1 5 10 26712PRTArtificial SequenceSynthetic Construct 267Arg Ala Ser Cys Asp Val Ser Ser Thr Tyr Leu Ala 1 5 10 2689PRTArtificial SequenceSynthetic Construct 268Gln Gln Tyr Met Arg Ser Pro Leu Thr 1 5 26912PRTArtificial SequenceSynthetic Construct 269Arg Ala Ser Glu Ala Val Pro Ser Thr Tyr Leu Ala 1 5 10 27012PRTArtificial SequenceSynthetic Construct 270Cys Ser Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala 1 5 10 27112PRTArtificial SequenceSynthetic Construct 271Arg Ala Ser Val Arg Val Ser Ser Thr Tyr Leu Ala 1 5 10 2729PRTArtificial SequenceSynthetic Construct 272Gln Gln Tyr Met Lys Trp Pro Leu Thr 1 5 27312PRTArtificial SequenceSynthetic Construct 273Arg Ala Ser Gln Ser Val Ser Ala Ala Tyr Leu Ala 1 5 10 2749PRTArtificial SequenceSynthetic Construct 274Gln Gln Tyr Met Cys Trp Pro Leu Thr 1 5 27512PRTArtificial SequenceSynthetic Construct 275Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Trp Gly 1 5 10 2769PRTArtificial SequenceSynthetic Construct 276Gln Gln Tyr Gln Cys Trp Pro Leu Thr 1 5 27712PRTArtificial SequenceSynthetic Construct 277Arg Ala Ser Gln Ser Val Ser Ser Pro Tyr Leu Ala 1 5 10 2789PRTArtificial SequenceSynthetic Construct 278Gln Gln Tyr Lys Ala Trp Pro Leu Thr 1 5 27912PRTArtificial SequenceSynthetic Construct 279Arg Ala Ser Gln Ser Val Ser Tyr Leu Tyr Leu Ala 1 5 10 2809PRTArtificial SequenceSynthetic Construct 280Gln Gln Tyr Met Glu Trp Pro Leu Thr 1 5 2819PRTArtificial SequenceSynthetic Construct 281Gln Gln Tyr Gln Ala Trp Pro Leu Thr 1 5 2829PRTArtificial SequenceSynthetic Construct 282Gln Gln Tyr Gln Lys Trp Pro Leu Thr 1 5 28312PRTArtificial SequenceSynthetic Construct 283Arg Ala Ser Gln Ser Val Ser Ala Val Tyr Leu Ala 1 5 10 2849PRTArtificial SequenceSynthetic Construct 284Gln Gln Tyr Arg Ala Trp Pro Leu Thr 1 5 28512PRTArtificial SequenceSynthetic Construct 285Arg Ala Ser Ile Ala Val Ser Ser Thr Tyr Leu Ala 1 5 10 2869PRTArtificial SequenceSynthetic Construct 286Gln Gln Tyr Met Val Trp Pro Leu Thr 1 5 28712PRTArtificial SequenceSynthetic Construct 287Arg Pro Arg Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 2889PRTArtificial SequenceSynthetic Construct 288Gln Gln Tyr Gln Asp Trp Pro Leu Thr 1 5 2899PRTArtificial SequenceSynthetic Construct 289Gln Gln Tyr Gln Glu Trp Pro Leu Thr 1 5 29012PRTArtificial SequenceSynthetic Construct 290Arg Ala Ser Gln Ser Val Ser Ala Ser Tyr Leu Ala 1 5 10 2919PRTArtificial SequenceSynthetic Construct 291Gln Gln Tyr Met Ser Trp Pro Leu Thr 1 5 29212PRTArtificial SequenceSynthetic Construct 292Arg Ala Ser Gln Ser Val Ser Tyr Met Tyr Leu Ala 1 5 10 2939PRTArtificial SequenceSynthetic Construct 293Gln Gln Tyr Lys Ser Trp Pro Leu Thr 1 5 2949PRTArtificial SequenceSynthetic Construct 294Gln Gln Tyr Tyr Gly Trp Pro Leu Thr 1 5 29512PRTArtificial SequenceSynthetic Construct 295Arg Ala Ser Gln Pro Ile Ser Ser Ser Tyr Leu Ala 1 5 10 2969PRTArtificial SequenceSynthetic Construct 296Gln Gln Tyr Glu Phe Trp Pro Leu Thr 1 5 29712PRTArtificial SequenceSynthetic Construct 297Arg Ala Ser Gln Gly Ile Ser Ser Thr Tyr Leu Ala 1 5 10 2989PRTArtificial SequenceSynthetic Construct 298Gln Gln Tyr Ala Tyr Trp Pro Leu Thr 1 5 29912PRTArtificial SequenceSynthetic Construct 299Arg Ala Ser Gln Ser Val Ser Val Arg Tyr Leu Ala 1 5 10 3009PRTArtificial SequenceSynthetic Construct 300Gln Gln Tyr Gly Ser Trp Pro Ile Thr 1 5 3015PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(3)..(3)Xaa is A or PMISC_FEATURE(5)..(5)Xaa is T, N, or S 301Ser Tyr Xaa Met Xaa 1 5 3027PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(5)..(5)Xaa is G or S 302Gly Phe Thr Phe Xaa Ser Tyr 1 5 30310PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(5)..(5)Xaa is G or SMISC_FEATURE(8)..(8)Xaa is A or PMISC_FEATURE(10)..(10)Xaa is T, N, or S 303Gly Phe Thr Phe Xaa Ser Tyr Xaa Met Xaa 1 5 10 30417PRTArtificial SequenceSynthetic Construct 304Ala Ile Ser Gly Trp Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 30517PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa is I, V, T, H, L, A, or CMISC_FEATURE(3)..(3)Xaa is S, D, G, T, I, L, F, M, or VMISC_FEATURE(4)..(4)Xaa is G, Y, L, H, D, A, S, or MMISC_FEATURE(5)..(5)Xaa is S, Q, T, A, F, or WMISC_FEATURE(7)..(7)Xaa is G or TMISC_FEATURE(8)..(8)Xaa is N, S, P, Y, W, or FMISC_FEATURE(9)..(9)Xaa is S, T, I, L, T, A, R, V, K, G, or CMISC_FEATURE(10)..(10)Xaa is F, Y, P, W, H, or GMISC_FEATURE(14)..(14)Xaa is V, R, or LMISC_FEATURE(15)..(15)Xaa is G or T 305Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa Lys 1 5 10 15 Gly 3066PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa is S, V, I, D, G, T, L, F, or MMISC_FEATURE(2)..(2)Xaa is G, Y, L, H, D, A,

S, or MMISC_FEATURE(3)..(3)Xaa is S, G, F, or WMISC_FEATURE(4)..(4)Xaa is G or SMISC_FEATURE(5)..(5)Xaa is G or TMISC_FEATURE(6)..(6)Xaa is N, S, P, Y, or W 306Xaa Xaa Xaa Xaa Xaa Xaa 1 5 30710PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(5)..(5)Xaa is A or YMISC_FEATURE(6)..(6)Xaa is A or SMISC_FEATURE(7)..(7)Xaa is G, Q, L, P, or E 307Val Ser Pro Ile Xaa Xaa Xaa Met Asp Tyr 1 5 10 3086PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(5)..(5)Xaa is D, S, T, or AMISC_FEATURE(6)..(6)Xaa is I, S, L, P, or D 308Tyr Trp Pro Met Xaa Xaa 1 5 30912PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa is R, G, W, A, or CMISC_FEATURE(2)..(2)Xaa is A, P, G, L, C, or SMISC_FEATURE(3)..(3)Xaa is S, G, or RMISC_FEATURE(4)..(4)Xaa is Q, C, E, V, or IMISC_FEATURE(5)..(5)Xaa is S, P, G, A, R, or DMISC_FEATURE(6)..(6)Xaa is V, G, I, or LMISC_FEATURE(7)..(7)Xaa is S, E, D, P, or GMISC_FEATURE(8)..(8)Xaa is S, P, F, A, M, E, V, N, D, or YMISC_FEATURE(9)..(9)Xaa is I, T, V, E, F, S, A, M, Q, Y, H, or RMISC_FEATURE(10)..(10)Xaa is Y or FMISC_FEATURE(11)..(11)Xaa is L, W, or PMISC_FEATURE(12)..(12)Xaa is A, S, or G 309Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 3107PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa is G or DMISC_FEATURE(4)..(4)Xaa is S or IMISC_FEATURE(7)..(7)Xaa is T or P 310Xaa Ala Ser Xaa Arg Ala Xaa 1 5 31110PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa is Q or KMISC_FEATURE(2)..(2)Xaa is H or YMISC_FEATURE(4)..(4)Xaa is G, N, or PMISC_FEATURE(5)..(5)Xaa is S, W, or Y 311Xaa Xaa Tyr Xaa Xaa Pro Pro Ser Phe Thr 1 5 10 3129PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(4)..(4)Xaa is G, Q, E, L, F, A, S, M, K, R, or YMISC_FEATURE(5)..(5)Xaa is S, R, T, G, V, F, Y, D, A, H, V, E, K, or CMISC_FEATURE(6)..(6)Xaa is W, F, or SMISC_FEATURE(8)..(8)Xaa is L or I 312Gln Gln Tyr Xaa Xaa Xaa Pro Xaa Thr 1 5 313119PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(30)..(30)Xaa is G or SMISC_FEATURE(33)..(33)Xaa is A or PMISC_FEATURE(35)..(35)Xaa is T, N, or SMISC_FEATURE(51)..(51)Xaa is I, V, T, H, L, A, or CMISC_FEATURE(52)..(52)Xaa is S, D, G, T, I, L, F, M, or VMISC_FEATURE(53)..(53)Xaa is G, Y, L, H, D, A, S, or MMISC_FEATURE(54)..(54)Xaa is S, Q, T, A, F, or WMISC_FEATURE(56)..(56)Xaa is G or TMISC_FEATURE(57)..(57)Xaa is N, S, P, Y, W, or FMISC_FEATURE(58)..(58)Xaa is S, T, I, L, T, A, R, V, K, G, or CMISC_FEATURE(59)..(59)Xaa is F, Y, P, W, H, or GMISC_FEATURE(63)..(63)Xaa is V, R, or LMISC_FEATURE(64)..(64)Xaa is G or TMISC_FEATURE(103)..(103)Xaa is A or YMISC_FEATURE(104)..(104)Xaa is A or SMISC_FEATURE(105)..(105)Xaa is G, Q, L, P, or E 313Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Ser Tyr 20 25 30 Xaa Met Xaa Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Ser Pro Ile Xaa Xaa Xaa Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 314115PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(30)..(30)Xaa is G or SMISC_FEATURE(33)..(33)Xaa is A or PMISC_FEATURE(35)..(35)Xaa is T, N, or SMISC_FEATURE(51)..(51)Xaa is I, V, T, H, L, A, or CMISC_FEATURE(52)..(52)Xaa is S, D, G, T, I, L, F, M, or VMISC_FEATURE(53)..(53)Xaa is G, Y, L, H, D, A, S, or MMISC_FEATURE(54)..(54)Xaa is S, Q, T, A, F, or WMISC_FEATURE(56)..(56)Xaa is G or TMISC_FEATURE(57)..(57)Xaa is N, S, P, Y, W, or FMISC_FEATURE(58)..(58)Xaa is S, T, I, L, T, A, R, V, K, G, or CMISC_FEATURE(59)..(59)Xaa is F, Y, P, W, H, or GMISC_FEATURE(63)..(63)Xaa is V, R, or LMISC_FEATURE(64)..(64)Xaa is G or TMISC_FEATURE(103)..(103)Xaa is D, S, T, or AMISC_FEATURE(104)..(104)Xaa is I, S, L, P, or D 314Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Ser Tyr 20 25 30 Xaa Met Xaa Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 315109PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(24)..(24)Xaa is R, G, W, A, or CMISC_FEATURE(25)..(25)Xaa is A, P, G, L, C, or SMISC_FEATURE(26)..(26)Xaa is S, G, or RMISC_FEATURE(27)..(27)Xaa is Q, C, E, V, or IMISC_FEATURE(28)..(28)Xaa is S, P, G, A, R, or DMISC_FEATURE(29)..(29)Xaa is V, G, I, or LMISC_FEATURE(30)..(30)Xaa is S, E, D, P, or GMISC_FEATURE(31)..(31)Xaa is S, P, F, A, M, E, V, N, D, or YMISC_FEATURE(32)..(32)Xaa is I, T, V, E, S, A, M, Q, Y, H, R, or FMISC_FEATURE(33)..(33)Xaa is Y or FMISC_FEATURE(34)..(34)Xaa is L, W, or PMISC_FEATURE(35)..(35)Xaa is A, S, or GMISC_FEATURE(51)..(51)Xaa is G or DMISC_FEATURE(54)..(54)Xaa is S or IMISC_FEATURE(57)..(57)Xaa is T or PMISC_FEATURE(90)..(90)Xaa is Q or KMISC_FEATURE(91)..(91)Xaa is H or YMISC_FEATURE(93)..(93)Xaa is G, N, or PMISC_FEATURE(94)..(94)Xaa is S, W, or Y 315Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Xaa Ala Ser Xaa Arg Ala Xaa Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Xaa Xaa Tyr Xaa Xaa Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 316107PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(24)..(24)Xaa is R, G, W, A, or CMISC_FEATURE(25)..(25)Xaa is A, P, G, L, C, or SMISC_FEATURE(26)..(26)Xaa is S, G, or RMISC_FEATURE(27)..(27)Xaa is Q, C, E, V, or IMISC_FEATURE(28)..(28)Xaa is S, L, P, G, A, R, or DMISC_FEATURE(29)..(29)Xaa is V, G, or IMISC_FEATURE(30)..(30)Xaa is S, E, D, or PMISC_FEATURE(31)..(31)Xaa is S, P, F, A, M, E, V, N, D, or YMISC_FEATURE(32)..(32)Xaa is I, T, V, E, S, A, M, Q, Y, H, or RMISC_FEATURE(33)..(33)Xaa is Y or FMISC_FEATURE(34)..(34)Xaa is L, W, or PMISC_FEATURE(35)..(35)Xaa is A, S, or GMISC_FEATURE(51)..(51)Xaa is G or DMISC_FEATURE(54)..(54)Xaa is S or IMISC_FEATURE(57)..(57)Xaa is T or PMISC_FEATURE(93)..(93)Xaa is G, Q, E, L, F, A, S, M, R, K, or YMISC_FEATURE(94)..(94)Xaa is S, R, T, G, R, V, D, A, H, E, K, C, F, or YMISC_FEATURE(95)..(95)Xaa is W, S, or FMISC_FEATURE(97)..(97)Xaa is L or I 316Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Xaa Ala Ser Xaa Arg Ala Xaa Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Xaa Xaa Xaa Pro 85 90 95 Xaa Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 317108PRTArtificial SequenceSynthetic Construct 317Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 3185PRTArtificial SequenceSynthetic Construct 318Leu Leu Gln Gly Gly 1 5 319112PRTArtificial SequenceSynthetic Construct 319Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 320121PRTArtificial SequenceSynthetic Construct 320Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 321112PRTArtificial SequenceSynthetic Construct 321Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 322121PRTArtificial SequenceSynthetic Construct 322Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 323112PRTArtificial SequenceSynthetic Construct 323Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 324121PRTArtificial SequenceSynthetic Construct 324Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 325112PRTArtificial SequenceSynthetic Construct 325Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 326121PRTArtificial SequenceSynthetic Construct 326Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 327112PRTArtificial

SequenceSynthetic Construct 327Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 328121PRTArtificial SequenceSynthetic Construct 328Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 329112PRTArtificial SequenceSynthetic Construct 329Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 330121PRTArtificial SequenceSynthetic Construct 330Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Pro 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 3315PRTArtificial SequenceSynthetic Construct 331Asp Tyr Tyr Met Thr 1 5 3327PRTArtificial SequenceSynthetic Construct 332Gly Phe Thr Phe Ser Asp Tyr 1 5 33310PRTArtificial SequenceSynthetic Construct 333Gly Phe Thr Phe Ser Asp Tyr Tyr Met Thr 1 5 10 33419PRTArtificial SequenceSynthetic Construct 334Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala Ser 1 5 10 15 Val Lys Gly 33510PRTArtificial SequenceSynthetic Construct 335Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr 1 5 10 33619PRTArtificial SequenceSynthetic Construct 336Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro Ser 1 5 10 15 Val Lys Gly 33719PRTArtificial SequenceSynthetic Construct 337Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 33819PRTArtificial SequenceSynthetic Construct 338Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Asp Ser 1 5 10 15 Val Lys Gly 33919PRTArtificial SequenceSynthetic Construct 339Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Pro Ser 1 5 10 15 Val Lys Gly 34017PRTArtificial SequenceSynthetic Construct 340Thr Ser Ser Gln Ser Leu Phe Asn Val Arg Ser Arg Lys Asn Tyr Leu 1 5 10 15 Ala 3417PRTArtificial SequenceSynthetic Construct 341Trp Ala Ser Thr Arg Glu Ser 1 5 3428PRTArtificial SequenceSynthetic Construct 342Lys Gln Ser Tyr Asp Leu Phe Thr 1 5 34317PRTArtificial SequenceSynthetic Construct 343Lys Ser Ser Gln Ser Leu Phe Asn Val Arg Ser Arg Lys Asn Tyr Leu 1 5 10 15 Ala 344112PRTArtificial SequenceSynthetic Construct 344Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 345121PRTArtificial SequenceSynthetic Construct 345Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 346112PRTArtificial SequenceSynthetic Construct 346Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 347121PRTArtificial SequenceSynthetic Construct 347Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 348112PRTArtificial SequenceSynthetic Construct 348Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 349121PRTArtificial SequenceSynthetic Construct 349Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 350112PRTArtificial SequenceSynthetic Construct 350Asp Ile Val Met Ser Gln Ser Pro Pro Ser Leu Ala Val Ser Val Gly 1 5 10 15 Asp Lys Val Thr Met Ser Cys Thr Ser Ser Gln Ser Leu Phe Asn Ser 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ser Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 351121PRTArtificial SequenceSynthetic Construct 351Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Phe Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Asn Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 352112PRTArtificial SequenceSynthetic Construct 352Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asp Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys Thr Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 353184PRTHomo sapien 353Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu 50 55 60 Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile 65 70 75 80 Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu 85 90 95 Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu 100 105 110 Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys 115 120 125 Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe 130 135 140 Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys 145 150 155 160 Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu 165 170 175 Ile Glu Lys Ser Ile Ser Ala Arg 180 354119PRTArtificial SequenceSynthetic Construct 354Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Ile Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe 50 55 60 Lys Asn Lys Ala Ile Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 355112PRTArtificial SequenceSynthetic Construct 355Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Lys Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 356117PRTArtificial SequenceSynthetic Construct 356Gln Val Gln Leu Gln

Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Glu Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Tyr Leu His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asn Arg Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 357215PRTArtificial SequenceSynthetic Construct 357Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro 85 90 95 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 358255PRTArtificial SequenceSynthetic Construct 358Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 3596PRTArtificial SequenceSynthetic Construct 359Ser Gly Ser Gly Gly Ser 1 5 36017PRTArtificial SequenceSynthetic Construct 360Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 3619PRTArtificial SequenceSynthetic Construct 361Val Gly Thr Ser Gly Ala Phe Gly Ile 1 5 3627PRTArtificial SequenceSynthetic Construct 362Gly Ala Ser Ser Arg Ala Tyr 1 5 363118PRTArtificial SequenceSynthetic Construct 363Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ser Trp Ser Gly Ala Phe Asp Asn Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 364109PRTArtificial SequenceSynthetic Construct 364Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro 85 90 95 Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 365118PRTArtificial SequenceSynthetic Construct 365Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Val Gly Thr Ser Gly Ala Phe Gly Ile Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 3665PRTArtificial SequenceSynthetic Construct 366Ser Tyr Ala Met Ser 1 5 36710PRTArtificial SequenceSynthetic Construct 367Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser 1 5 10 3686PRTArtificial SequenceSynthetic Construct 368Ser Ala Ser Gly Gly Ser 1 5 36917PRTArtificial SequenceSynthetic Construct 369Ala Ile Ser Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly 3709PRTArtificial SequenceSynthetic Construct 370Leu Ser Trp Ser Gly Ala Phe Asp Asn 1 5 3717PRTArtificial SequenceSynthetic Construct 371Gly Phe Thr Phe Arg Ser Tyr 1 5 37210PRTArtificial SequenceSynthetic Construct 372Gly Phe Thr Phe Arg Ser Tyr Ala Met Ser 1 5 10 373112PRTArtificial SequenceSynthetic Construct 373Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asp Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys Thr Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 374119PRTArtificial SequenceSynthetic Construct 374Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Ile Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe 50 55 60 Lys Asn Lys Ala Ile Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 375112PRTArtificial SequenceSynthetic Construct 375Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Ala Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Lys Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 376117PRTArtificial SequenceSynthetic Construct 376Gln Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Glu Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Tyr Leu His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asn Arg Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 377109PRTArtificial SequenceSynthetic Construct 377Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Ala Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Asn Asn 85 90 95 Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 378124PRTArtificial SequenceSynthetic Construct 378Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Glu Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Leu Ser Met 65 70 75 80 Val Tyr Leu Gln Met Asn Ser Leu Lys Asn Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 379109PRTArtificial SequenceSynthetic Construct 379Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45 Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala 65 70 75 80 Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 380124PRTArtificial SequenceSynthetic Construct 380Glu Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Arg 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 381109PRTArtificial SequenceSynthetic Construct 381Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 382124PRTArtificial SequenceSynthetic Construct 382Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 383109PRTArtificial SequenceSynthetic Construct 383Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 384124PRTArtificial SequenceSynthetic Construct 384Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 385109PRTArtificial SequenceSynthetic Construct 385Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ala Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 386124PRTArtificial SequenceSynthetic Construct 386Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 387109PRTArtificial SequenceSynthetic Construct 387Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 388124PRTArtificial SequenceSynthetic Construct 388Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 389109PRTArtificial SequenceSynthetic Construct 389Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 390124PRTArtificial SequenceSynthetic Construct 390Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 391109PRTArtificial SequenceSynthetic Construct 391Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 392124PRTArtificial SequenceSynthetic Construct 392Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 393109PRTArtificial SequenceSynthetic Construct 393Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 394124PRTArtificial SequenceSynthetic Construct 394Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser His Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 395109PRTArtificial SequenceSynthetic Construct 395Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 396124PRTArtificial SequenceSynthetic Construct 396Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 397109PRTArtificial SequenceSynthetic Construct 397Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 398124PRTArtificial SequenceSynthetic Construct 398Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Glu Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 399109PRTArtificial SequenceSynthetic Construct 399Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn 85 90 95 His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 400124PRTArtificial SequenceSynthetic Construct 400Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Lys Thr Tyr Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala 100 105 110 Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 4015PRTArtificial SequenceSynthetic

Construct 401Thr Tyr Ala Met Asn 1 5 4027PRTArtificial SequenceSynthetic Construct 402Gly Phe Thr Phe Asn Thr Tyr 1 5 40310PRTArtificial SequenceSynthetic Construct 403Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn 1 5 10 4048PRTArtificial SequenceSynthetic Construct 404Arg Ser Lys Ile Asn Asn Tyr Ala 1 5 40519PRTArtificial SequenceSynthetic Construct 405Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 40613PRTArtificial SequenceSynthetic Construct 406His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala Ser 1 5 10 4077PRTArtificial SequenceSynthetic Construct 407Gly Phe Thr Phe Ser Thr Tyr 1 5 40810PRTArtificial SequenceSynthetic Construct 408Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn 1 5 10 4098PRTArtificial SequenceSynthetic Construct 409Arg Ser His Ile Asn Asn Tyr Ala 1 5 41019PRTArtificial SequenceSynthetic Construct 410Arg Ile Arg Ser His Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 4118PRTArtificial SequenceSynthetic Construct 411Arg Ser Lys Tyr Asn Asn Tyr Ala 1 5 41219PRTArtificial SequenceSynthetic Construct 412Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 41319PRTArtificial SequenceSynthetic Construct 413Arg Glu Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 41419PRTArtificial SequenceSynthetic Construct 414Arg Ile Arg Ser Lys Ile Asn Asn Tyr Lys Thr Tyr Tyr Ala Glu Ser 1 5 10 15 Val Lys Gly 4157PRTArtificial SequenceSynthetic Construct 415Gly Phe Thr Phe Thr Asp Tyr 1 5 41610PRTArtificial SequenceSynthetic Construct 416Gly Phe Thr Phe Thr Asp Tyr Tyr Met Thr 1 5 10 4178PRTArtificial SequenceSynthetic Construct 417Arg Asn Arg Ala Arg Gly Tyr Thr 1 5 41819PRTArtificial SequenceSynthetic Construct 418Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala Ser 1 5 10 15 Val Lys Gly 4197PRTArtificial SequenceSynthetic Construct 419Gly Tyr Thr Phe Thr Ser Tyr 1 5 42010PRTArtificial SequenceSynthetic Construct 420Gly Tyr Thr Phe Thr Ser Tyr Trp Met His 1 5 10 4216PRTArtificial SequenceSynthetic Construct 421Tyr Ser Gly Gly Asp Thr 1 5 42217PRTArtificial SequenceSynthetic Construct 422Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe Lys 1 5 10 15 Asn 42310PRTArtificial SequenceSynthetic Construct 423Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr 1 5 10 4245PRTArtificial SequenceSynthetic Construct 424Thr Tyr Tyr Leu His 1 5 4258PRTArtificial SequenceSynthetic Construct 425Gly Tyr Ser Phe Thr Thr Tyr Tyr 1 5 42610PRTArtificial SequenceSynthetic Construct 426Gly Tyr Ser Phe Thr Thr Tyr Tyr Leu His 1 5 10 4276PRTArtificial SequenceSynthetic Construct 427Phe Pro Gly Ser Asp Asn 1 5 42817PRTArtificial SequenceSynthetic Construct 428Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly 4298PRTArtificial SequenceSynthetic Construct 429Asn Arg Asp Tyr Tyr Phe Asp Tyr 1 5 43017PRTArtificial SequenceSynthetic Construct 430Thr Ser Ser Gln Ser Leu Phe Asn Ser Arg Ser Arg Lys Asn Tyr Leu 1 5 10 15 Ala 43115PRTArtificial SequenceSynthetic Construct 431Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr 1 5 10 15 4328PRTArtificial SequenceSynthetic Construct 432Thr Gln Ser Phe Ile Leu Arg Thr 1 5 4337PRTArtificial SequenceSynthetic Construct 433Trp Ala Ser Thr Arg Ala Ser 1 5 4348PRTArtificial SequenceSynthetic Construct 434Lys Gln Ser Phe Ile Leu Arg Thr 1 5 43514PRTArtificial SequenceSynthetic Construct 435Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn 1 5 10 4367PRTArtificial SequenceSynthetic Construct 436Gly Thr Asn Thr Arg Ala Pro 1 5 4379PRTArtificial SequenceSynthetic Construct 437Val Leu Trp Tyr Asn Asn Tyr Trp Val 1 5 4389PRTArtificial SequenceSynthetic Construct 438Ala Leu Trp Tyr Ser Asn His Trp Val 1 5 4399PRTArtificial SequenceSynthetic Construct 439Val Leu Trp Tyr Asn Asn His Trp Val 1 5 44014PRTArtificial SequenceSynthetic Construct 440Arg Ala Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn 1 5 10 44114PRTArtificial SequenceSynthetic Construct 441Arg Thr Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn 1 5 10 442117PRTArtificial SequenceSynthetic Construct 442Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Leu Val Lys Leu Ser Cys Lys Gly Ser Gly Phe Asn Ile Lys Asp Tyr 20 25 30 Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Asp Pro Glu Asn Gly Asn Asn Lys Tyr Asp Pro Lys Phe 50 55 60 Gln Gly Lys Ala Ser Ile Thr Ala Asp Thr Ser Ser Asn Ile Ala Tyr 65 70 75 80 Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Asp Asn Tyr Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 443112PRTArtificial SequenceSynthetic Construct 443Asp Ile Val Val Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Ile Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Leu Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Thr Glu Asp Leu Ala Val Tyr Tyr Cys Met Gln 85 90 95 Ser Phe Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 444121PRTArtificial SequenceSynthetic Construct 444Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 445112PRTArtificial SequenceSynthetic Construct 445Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Ser 20 25 30 Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Asp Thr Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 4465PRTArtificial SequenceSynthetic Construct 446Asp Tyr Tyr Ile His 1 5 4477PRTArtificial SequenceSynthetic Construct 447Gly Phe Asn Ile Lys Asp Tyr 1 5 44810PRTArtificial SequenceSynthetic Construct 448Gly Phe Asn Ile Lys Asp Tyr Tyr Ile His 1 5 10 4496PRTArtificial SequenceSynthetic Construct 449Asp Pro Glu Asn Gly Asn 1 5 45017PRTArtificial SequenceSynthetic Construct 450Trp Ile Asp Pro Glu Asn Gly Asn Asn Lys Tyr Asp Pro Lys Phe Gln 1 5 10 15 Gly 4518PRTArtificial SequenceSynthetic Construct 451Asn Asp Asn Tyr Ala Phe Asp Tyr 1 5 4527PRTArtificial SequenceSynthetic Construct 452Ser Ala Ser Thr Arg Glu Ser 1 5 4538PRTArtificial SequenceSynthetic Construct 453Met Gln Ser Phe Thr Leu Arg Thr 1 5 4544PRTArtificial SequenceSynthetic Construct 454Leu Leu Gln Gly 1 4556PRTArtificial SequenceSynthetic Construct 455Leu Ser Leu Ser Gln Gly 1 5 4568PRTArtificial SequenceSynthetic Construct 456Gly Gly Gly Leu Leu Gln Gly Gly 1 5 4575PRTArtificial SequenceSynthetic Construct 457Gly Leu Leu Gln Gly 1 5 45810PRTArtificial SequenceSynthetic Construct 458Gly Ser Pro Leu Ala Gln Ser His Gly Gly 1 5 10 4597PRTArtificial SequenceSynthetic Construct 459Gly Leu Leu Gln Gly Gly Gly 1 5 4606PRTArtificial SequenceSynthetic Construct 460Gly Leu Leu Gln Gly Gly 1 5 4614PRTArtificial SequenceSynthetic Construct 461Gly Leu Leu Gln 1 4628PRTArtificial SequenceSynthetic Construct 462Leu Leu Gln Leu Leu Gln Gly Ala 1 5 4635PRTArtificial SequenceSynthetic Construct 463Leu Leu Gln Gly Ala 1 5 4647PRTArtificial SequenceSynthetic Construct 464Leu Leu Gln Tyr Gln Gly Ala 1 5 4656PRTArtificial SequenceSynthetic Construct 465Leu Leu Gln Gly Ser Gly 1 5 4666PRTArtificial SequenceSynthetic Construct 466Leu Leu Gln Tyr Gln Gly 1 5 4677PRTArtificial SequenceSynthetic Construct 467Leu Leu Gln Leu Leu Gln Gly 1 5 4685PRTArtificial SequenceSynthetic Construct 468Ser Leu Leu Gln Gly 1 5 4695PRTArtificial SequenceSynthetic Construct 469Leu Leu Gln Leu Gln 1 5 4706PRTArtificial SequenceSynthetic Construct 470Leu Leu Gln Leu Leu Gln 1 5 4715PRTArtificial SequenceSynthetic Construct 471Leu Leu Gln Gly Arg 1 5 4726PRTArtificial SequenceSynthetic Construct 472Leu Leu Gln Gly Pro Pro 1 5 4736PRTArtificial SequenceSynthetic Construct 473Leu Leu Gln Gly Pro Ala 1 5 4748PRTArtificial SequenceSynthetic Construct 474Gly Gly Leu Leu Gln Gly Pro Pro 1 5 4757PRTArtificial SequenceSynthetic Construct 475Gly Gly Leu Leu Gln Gly Ala 1 5 4767PRTArtificial SequenceSynthetic Construct 476Leu Leu Gln Gly Pro Gly Lys 1 5 4776PRTArtificial SequenceSynthetic Construct 477Leu Leu Gln Gly Pro Gly 1 5 4785PRTArtificial SequenceSynthetic Construct 478Leu Leu Gln Gly Pro 1 5 4794PRTArtificial SequenceSynthetic Construct 479Leu Leu Gln Pro 1 4806PRTArtificial SequenceSynthetic Construct 480Leu Leu Gln Pro Gly Lys 1 5 4817PRTArtificial SequenceSynthetic Construct 481Leu Leu Gln Ala Pro Gly Lys 1 5 4827PRTArtificial SequenceSynthetic Construct 482Leu Leu Gln Gly Ala Pro Gly 1 5 4836PRTArtificial SequenceSynthetic Construct 483Leu Leu Gln Gly Ala Pro 1 5 4846PRTArtificial SequenceSynthetic Construct 484Leu Leu Gln Leu Gln Gly 1 5 485255DNAArtificial SequenceSynthetic Construct 485gagatcgtgc tgactcagtc ccctggaacc ctgtccctgt cacctggcga aagagctacc 60ttgtcctgtc gcgcatcaca atccgtgtcg tcgagctatc tcgcgtggta ccagcagaag 120cccggacagg ccccaaggct gcttatgtac gacgcctcca tccgggccac tggtatcccc 180gaccgcttct cgggctccgg aagcggcacc gacttcaccc tgactatttc ccggctcgaa 240ccggaggatt tcgcc 255486255DNAArtificial SequenceSynthetic Construct 486gaagtccaac tcctcgaatc cggtggcggc cttgtccagc ctggaggttc cttgcgcctg 60tcatgtgccg ccagcggatt caccttctcg tcctacccga tgtcgtgggt ccgccaggct 120ccgggaaagg gcctggaatg ggtgtcagcc atcggaggat cggggggctc cctgccctac 180gccgatatcg tgaagggaag gttcaccatt agccgggaca actccaagaa cactctgtac 240ctccaaatga acagc 255487255DNAArtificial SequenceSynthetic Construct 487gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctccaggcga aagagccacc 60ctgtcctgca gagccagcca gagcgtgtcc agcagctacc tggcctggta tcagcagaag 120cccggccagg ctccccggct gctgatctat ggcgcctctt ctagagccac cggcatcccc 180gatagattca gcggctctgg cagcggcacc gacttcaccc tgaccatcag cagactggaa 240cccgaggact tcgcc 255488255DNAArtificial SequenceSynthetic Construct 488gaagtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 60tcttgtgccg ccagcggctt caccttcggc agctacgcta tgacctgggt gcgccaggcc 120cctggcaaag gactggaatg ggtgtccgcc atctctggca gcggcggcaa taccttctac 180gccgagagcg tgaagggccg gttcaccatc agccgggaca acagcaagaa caccctgtac 240ctgcagatga acagc 255489255DNAArtificial SequenceSynthetic Construct 489gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctcctggtga aagagctact 60ttgtcttgta gagcttctca atccgtttcc gcgtattatt tggcttggta tcaacaaaaa 120ccaggtcaag ctccaagatt attgatgtac gatgcttcta ttagagccac cggtattcca 180gatagatttt ctggttctgg ttccggtact gatttcactt tgactatctc tagattggaa 240ccagaagatt tcgct 255490255DNAArtificial SequenceSynthetic Construct 490gaagttcaat tattggaatc tggtggagga ctggtgcagc ctggcggctc tctgagactg 60tcttgtgccg ccagcggctt caccttcagc agctacgcca tgaactgggt gcgccaggcc 120cctggtaaag gtttggaatg ggtttctgct attactgcgt ctggtggttc tacttactat 180gccgatgtgg ttaagggtag attcaccatt tctagagaca actctaagaa caccttgtac 240ttgcaaatga actcc 255491255DNAArtificial SequenceSynthetic Construct 491gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctcctggtga aagagctact 60ttgtcttgta gagcttctca atccgtttcc gatctgtatt tggcttggta tcaacaaaaa 120ccaggtcaag ctccaagatt attgatgtac gatgcttcta ttagagccac cggtattcca 180gatagatttt ctggttctgg ttccggtact gatttcactt tgactatctc tagattggaa 240ccagaagatt tcgct 255492255DNAArtificial SequenceSynthetic Construct 492gaagttcaat tattggaatc tggtggagga ctggtgcagc ctggcggctc tctgagactg 60tcttgtgccg ccagcggctt caccttcagc agctacgcca tgaactgggt gcgccaggcc 120cctggtaaag gtttggaatg ggtttctgct atttctgatt ttggtggttc tacttactat 180gccgatatcg ttaagggtag attcaccatt tctagagaca actctaagaa caccttgtac 240ttgcaaatga actcc 255493255PRTHomo sapien 493Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 494255PRTHomo sapien 494Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 245 250 255 495255PRTHomo sapien 495Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 245 250 255 496255PRTArtificial SequenceSynthetic Construct 496Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Arg Val Arg Cys Pro Arg Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 497255PRTArtificial SequenceSynthetic Construct 497Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Glu Val Glu Cys Pro Glu Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Glu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 49815PRTArtificial SequenceSynthetic Construct 498Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 49910PRTArtificial SequenceSynthetic Construct 499Gln His Tyr Gly Ser Pro Pro Leu Phe Thr 1 5 10 50012PRTArtificial SequenceSynthetic Construct 500Arg Ala Ser Gln Asn Val Ser Ser Ser Tyr Leu Ala 1 5 10 5017PRTArtificial SequenceSynthetic Construct 501Gly Ala Ser Tyr Arg Ala Thr 1 5 502198PRTHomo sapiens 502Met Gln Ser Gly Thr Arg Trp Arg Val Leu Gly Leu Cys Leu Leu Ser 1 5 10 15 Ile Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Ser Ile Thr 20 25 30 Gln Thr Pro Tyr Gln Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr 35 40 45 Cys Ser Gln His Leu Gly Ser Glu Ala Gln Trp Gln His Asn Gly Lys 50 55 60 Asn Lys Glu Asp Ser Gly Asp Arg Leu Phe Leu Pro Glu Phe Ser Glu 65 70 75 80 Met Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Asn Pro 85 90 95 Glu Asp Ala Ser His His Leu Tyr Leu Lys Ala Arg Val Cys Glu Asn 100 105 110 Cys Met Glu Met Asp Val Met Ala Val Ala Thr Ile Val Ile Val Asp 115 120 125 Ile Cys Ile Thr Leu Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys 130 135 140 Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala Gly 145 150 155 160 Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro Asn 165 170 175 Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Gln Asp Leu Tyr Ser Gly 180 185 190 Leu Asn Gln Arg Arg Ile 195

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